Diaryl ethers as opioid receptor antagonist

ABSTRACT

A compound of the formula (I) wherein the variables X 1  to X 10 , R 1  to R 7  including R 3′ , E, v, y, z, A and B are as described, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof, useful for the treatment, prevention or amelioration of obesity and Related Diseases is disclosed

This application claims priority from PCT Application No.PCT/US2003/026300, filed Sep. 17, 2003 which further claims priorityfrom U.S. Provisional Application No. 60/412,158, filed Sep. 19, 2002.

The present invention is in the field of medicinal chemistry. Theinvention relates specifically to compounds useful as opioidantagonists, methods of treatment, methods of using, and pharmaceuticalcompositions thereof.

BACKGROUND

Three types of opioid receptors, mu, kappa, and delta opioid receptorsare generally reported. Recent evidence points to the interactionsbetween receptor dimer combinations of mu, kappa and/or delta receptors(called heterodimers) as also contributing to opioid activity. Opioidreceptors and their normal regulation or lack thereof, has beenimplicated in disease states including irritable bowel syndrome, nausea,vomiting, pruritic dermatoses, depression, smoking and alcoholaddiction, sexual dysfunction, stroke and trauma in animals. Thereforeit is not surprising that the ability to antagonistically bind opioidreceptors has been shown to produce ameliorative, preventative and/ortreatment effects in animals including humans afflicted with one or moreof these disease states.

More recently, certain antagonists of the opioid receptors have beenfound to increase metabolic energy consumption, and reduction of weightin obese rats while maintaining muscle mass. These findings indicatethat an effective opioid antagonist may be useful in preventing,treating and/or ameliorating the effect of obesity. Considering thepercentage of the population that is obese in Western societies and theindirect costs associated with treating the effects and symptoms ofobesity and Related Diseases, the importance of these findings cannot beoverstated.

Though many opioid antagonists have been disclosed, the search continuesfor alternative and/or improved or more effective antagonists having anoverall benefit to the patient with little or no major side effects.U.S. Pat. No. 4,891,379 disclosed phenylpiperidine opioid antagonistsuseful for the treatment of diabetes and obesity. In particular, U.S.Pat. No. 4,891,379 disclosed the compound LY 255582 represented by thestructure:

U.S. Pat. No. 4,191,771 also disclosed compounds useful as opioidantagonists. Also, bicyclic analogs of phenyl piperidine have beenprepared and reported as opioid antagonists in Wentland, et al.,Biorganic and Medicinal Chemistry Letters 11 (2001) 623-626; see alsoWentland, et al., Bioorganic and Medicinal Chemistry Letters 11 (2001)1717-1721. Finally, European Patent application number EP 1 072592A2filed May 18, 2000, discloses phenylpiperidine compounds of formula I

wherein A, D, R¹, R², R³, X, and n have meanings given in thedescription, which are useful in the prophylaxis and in the treatment ofdiseases mediated by opioid receptors such as pruritus.

U.S. Pat. No. 6,140,352 and related patents disclose the compound offormula Formula I

wherein the variables X₁, X₂, X₃ R₁, R₃, R₄, R₅ and R₆ are as describedtherein, as agonists of the beta adrenergic receptor useful for thetreatment of diabetes and obesity.

Regardless of these and other disclosures of compounds useful as opioidreceptor antagonists, or useful for the treatment of obesity, and/ordiabetes by other mechanisms, there remains an unmet medical need for asafe, effective and/or alternate treatment or prophylaxis of diseasesassociated with opioid receptors, particularly obesity and RelatedDiseases.

SUMMARY OF THE INVENTION

The present invention provides a compound of the formula (I)

wherein

-   each of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀ is C, CH, or N;    provided that each of rings A or B has no more than 2 nitrogen    atoms;-   E is O or NH;-   v is 1, 2, or 3;-   R¹ and R² are independently selected from hydrogen, C₁-C₈ alkyl,    C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₃-C₈ cycloalkyl, —C₁-C₁₀    alkylaryl, heterocyclyl, —C₁-C₁₀ alkylheterocyclic,    -arylheterocyclyl, —C₃-C₈ cycloalkylheterocyclyl, —C₁-C₈    alkylC(O)C₁-C₈ alkyl, aryl C(O)C₁-C₈ alkyl-, C₃-C₈    cycloalkylC(O)(CH₂)_(n)—, —C₂-C₈ alkylCH(OH)aryl, —C₂-C₈    alkylCH(OH)cycloalkyl, —C₂-C₈ alkylCH(OH)heterocyclyl, C₂-C₈    alkylCH(OH)aryl, —C₁-C₈ alkylC(O)heterocyclic, —C₁-C₈ alkylC(O)aryl,    aryloxyC₁-C₈ alkyl-, benzhydryl, fused bicyclic, C₁-C₈ alkyl fused    bicyclic, phenylC(O)—, phenylC(O)C₁-C₈ alkyl-, C₁-C₈ alkoxyC₁-C₈    alkyl-, —CO(O)C₁-C₈ alkyl, —SO₂C₁-C₈ alkyl, —SO₂C₁-C₁₀ alkylaryl,    —SO₂C₁-C₈ alkylheterocyclic, —C₁-C₈ alkylcycloalkyl,    —(CH₂)_(n)C(O)OR⁸, —(CH₂)_(n)C(O)R⁸, —(CH₂)_(m)C(O)NR⁸R⁸, and    —(CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, cycloalkyl,    heterocyclic, and aryl groups are optionally substituted with one to    five groups independently selected from halo, C₁-C₈ haloalkyl, C₁-C₈    thioalkyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, aryl, —C₁-C₈ alkylaryl,    —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈ alkyl, —SO₂C₁-C₈ alkyl, —SO₂C₁-C₈    alkylaryl, —SO₂C₁-C₈ alkylheterocyclic, —C₁-C₈ alkylcycloalkyl,    —(CH₂)_(n)C(O)OR⁸, —(CH₂)_(n)C(O)R⁸; and wherein R¹ and R² may    optionally combine with each other, or with 1, or 2 atoms adjacent    to the nitrogen atom to form a 4, 5, 6, or 7-membered    nitrogen-containing heterocycle which nitrogen-containing    heterocycle may further have substituents selected from the group    consisting of amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    aryl, C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈ alkyl, halo,    oxo, C₁-C₈ haloalkyl; and wherein R¹ and R² may independently attach    to the A ring to form a 4, 5, 6, or 7-member nitrogen-containing    bicyclic heterocycle which nitrogen-containing bicyclic heterocycle    may further have substituents selected from the group consisting of    oxo, amino, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, aryl,    —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈ alkyl, halo, and    C₁-C₈ haloalkyl; and wherein R¹ and R² are not simultaneously    hydrogen; and provided that when v is 2, and R³ and R^(3′) are both    hydrogen or CH₃, and both A and B rings are phenyl, then the group    —NR¹R² is not equal to —NHCH₂Phenyl; and further provided that when    one of R¹ or R² is —CH₂CH₂-optionally substituted phenyl or    —CH₂CH₂-optionally substituted naphthyl, or —CH₂CH₂-optionally    substituted 5 or 6 member monocyclic heterocyclic aromatic, and v is    1, and both A and B rings are phenyl, then R⁶ and R⁷ are not    simultaneously hydrogen;-   R³ and R^(3′) are each independently selected from hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, —C₁-C₈ alkylcycloalkyl,    and —C₁-C₈ alkylaryl;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, —C₂-C₈ alkynyl, —C₁-C₈ alkoxyalkyl, C₁-C₈    thioalkyl, halo, C₁-C₈ haloalkyl, —C₁-C₈ alkoxyhaloalkyl, aryl,    —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl, —C₁-C₈    alkylamino, —C₁-C₈ alkylcycloalkyl, —(CH₂)_(m)C(O)C₁-C₈ alkyl, and    (CH₂)_(n)NR⁸R⁸, wherein each R⁴ or R⁵ is attached to its respective    ring only at carbon atoms, and wherein y is 0, 1, 2, or 3; and    wherein z is 0, 1, 2, or 3;-   R⁶ and R⁷ are each independently selected from hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, —C(O)C₁-C₈ alkyl, hydroxy,    C₁-C₈ alkoxy, —SO₂C₁-C₈ alkyl, SO₂C₁-C₈ alkylaryl, —SO₂C₁-C₈    alkylheterocyclic, aryl, —C₁-C₈ alkylaryl, C₃-C₇ cycloalkyl, —C₁-C₆    alkylcycloalkyl, —(CH₂)_(n)C(O)R⁸, —(CH₂)_(m)C(O)NR⁸R⁸, and    —(CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, and aryl    groups are optionally substituted with one to five groups    independently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, aryl, and    C₁-C₈ alkylaryl; and wherein R⁶ and R⁷ may independently combine    with each other, and with the nitrogen atom to which they are    attached or with 1, or 2 atoms adjacent to the nitrogen atom to form    a 4, 5, 6, or 7-membered nitrogen containing heterocycle which    nitrogen containing heterocycle may optionally have substituents    selected from the group consisting of oxo, C₁-C₈ alkyl, C₂-C₈    alkenyl, C₂-C₈ alkynyl, aryl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl,    —CO(O)C₁-C₈ alkyl, hydroxy, C₁-C₈ alkoxy, —C₁-C₈ alkylamine, amino,    halo, and haloalkyl;-   R⁸ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkylaryl,    —C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl; and wherein n is 0, 1, 2, 3    or 4 and m is 1, 2, or 3;-   or a pharmaceutically acceptable salt, solvate, enantiomer,    racemate, diastereomer or mixture of diastereomers thereof.

The present invention also provides a method for the prevention,treatment and/or amelioration of the symptoms of obesity and RelatedDiseases comprising administering a therapeutically effective amount ofa compound of formula II to a patient in need thereof wherein formula IIis represented by the structure

wherein

-   each of X_(1′), X_(2′), X_(3′), X_(4′), X_(5′), X_(6′), X_(7′),    X_(8′), X_(9′), and X_(10′) is C, CH, or N; provided that each of    rings A′ or B′ has no more than 2 nitrogen atoms;-   E′ is O or NH;-   v is 0, 1, 2 or 3;-   R^(1′) and R^(2′) are independently selected from hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₃-C₈ cycloalkyl, —C₁-C₁₀    alkylaryl, heterocyclyl, —C₁-C₁₀ alkylheterocyclic,    -arylheterocyclyl, —C₃-C₈ cycloalkylheterocyclyl, —C₁-C₈    alkylC(O)C₁-C₈ alkyl, aryl C(O)C₁-C₈ alkyl-, C₃-C₈    cycloalkylC(O)(CH₂)_(n)—, —C₂-C₈ alkylCH(OH)aryl, —C₂-C₈    alkylCH(OH)cycloalkyl, —C₂-C₈ alkylCH(OH)heterocyclyl, C₂-C₈    alkylCH(OH)aryl, —C₁-C₈ alkylC(O)heterocyclic, —C₁-C₈ alkylC(O)aryl,    aryloxyC₁-C₈ alkyl-, benzhydryl, fused bicyclic, C₁-C₈ alkyl fused    bicyclic, phenylC(O)—, phenylC(O)C₁-C₈ alkyl-, C₁-C₈ alkoxyC₁-C₈    alkyl-, —CO(O)C₁-C₈ alkyl, —SO₂C₁-C₈ alkyl, —SO₂C₁-C₁₀ alkylaryl,    —SO₂C₁-C₈ alkylheterocyclic, —C₁-C₈ alkylcycloalkyl,    —(CH₂)_(n)C(O)OR⁸, —(CH₂)_(n)C(O)R⁸, —(CH₂)_(m)C(O)NR⁸R⁸, and    —(CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, cycloalkyl,    heterocyclic, and aryl groups are optionally substituted with one to    five groups independently selected from halo, C₁-C₈ haloalkyl, C₁-C₈    thioalkyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, aryl, —C₁-C₈ alkylaryl,    —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈ alkyl, —SO₂C₁-C₈ alkyl, —SO₂C₁-C₈    alkylaryl, —SO₂C₁-C₈ alkylheterocyclic, —C₁-C₈ alkylcycloalkyl,    —(CH₂)_(n)C(O)OR⁸, —(CH₂)_(n)C(O)R⁸; and wherein R^(1′) and R^(2′)    may optionally combine with each other, or with 1, or 2 atoms    adjacent to the nitrogen atom to form a 4, 5, 6, or 7-membered    nitrogen-containing heterocycle which nitrogen-containing    heterocycle may further have substituents selected from the group    consisting of amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    aryl, C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈ alkyl, halo,    oxo, C₁-C₈ haloalkyl; and wherein R^(1′) and R² may independently    attach to the A′ ring to form a 4, 5, 6, or 7-member    nitrogen-containing bicyclic heterocycle which nitrogen-containing    bicyclic heterocycle may further have substituents selected from the    group consisting of oxo, amino, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈    alkynyl, aryl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —CO(O)C₁-C₈    alkyl, halo, and C₁-C₈ haloalkyl; provided that R^(1′) and R^(2′)    are not simultaneously hydrogen; and provided that when v is 2, and    R^(3a) and R^(3b) are both hydrogen or CH₃, and both A′ and B′ rings    are phenyl, then the group —NR^(1′)R^(2′) is not equal to    —NHCH₂Phenyl; and further provided that when one of R^(1′) or R^(2′)    is —CH₂CH₂-optionally substituted phenyl or —CH₂CH₂-optionally    substituted naphthyl, or —CH₂CH₂-optionally substituted 5 or 6    member monocyclic heterocyclic aromatic, and v is 1, and both A′ and    B′ rings are phenyl, then R^(6′) and R^(7′) are not simultaneously    hydrogen;-   R^(3a) and R^(3b) are each independently selected from hydrogen,    C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, —C₁-C₈    alkylcycloalkyl, aryl, and —C₁-C₈ alkylaryl;-   R^(4′) and R^(5′) are each independently selected from hydrogen,    C₁-C₈ alkyl, C₂-C₈ alkenyl, —C₂-C₈ alkynyl, —C₁-C₈ alkoxyalkyl,    C₁-C₈ thioalkyl, halo, C₁-C₈ haloalkyl, —C₁-C₈ alkoxyhaloalkyl,    aryl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl,    —C₁-C₈ alkylamino, —C₁-C₈ alkylcycloalkyl, —(CH₂)_(m)C(O)C₁-C₈    alkyl, and —(CH₂)_(n)NR⁸R⁸, wherein each R^(4′) and R^(5′) is    attached to its respective ring only at carbon atoms, and wherein y    is 0, 1, 2, or 3; and wherein z is 0, 1, 2, or 3;-   R^(6′) and R^(7′) are each independently selected from hydrogen,    C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, —C(O)C₁-C₈ alkyl,    hydroxy, C₁-C₈ alkoxy, —SO₂C₁-C₈ alkyl, SO₂C₁-C₈ alkylaryl,    —SO₂C₁-C₈ alkylheterocyclic, aryl, —C₁-C₈ alkylaryl, C₃-C₇    cycloalkyl, —C₁-C₆ alkylcycloalkyl, —(CH₂)_(n)C(O)R⁸,    —(CH₂)_(m)C(O)NR⁸R⁸, and —(CH₂)_(m)NSO₂R⁸; wherein each of the    alkyl, alkenyl, and aryl groups are optionally substituted with one    to five groups independently selected from C₁-C₈ alkyl, C₂-C₈    alkenyl, aryl, and C₁-C₈ alkylaryl; and wherein R^(6′) and R^(7′)    may independently combine together, and with the nitrogen atom to    which they are attached or with 1, or 2 atoms adjacent to the    nitrogen atom to form a 4, 5, 6, or 7-membered nitrogen containing    heterocycle which nitrogen containing heterocycle may further have    substituents selected from the group consisting of C₁-C₈ alkyl,    C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈    alkyl, —CO(O)C₁-C₈ alkyl, hydroxy, —C₁-C₈ alkoxy, halo, and    haloalkyl;-   R⁸ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkylaryl,    —C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl; wherein n is 0, 1, 2, 3 or 4    and wherein m is 1, 2 or 3;-   or a pharmaceutically acceptable salt, solvate, enantiomer,    racemate, diastereomers or mixtures thereof.

The present invention also provides a pharmaceutical formulationcomprising a compound of formula I or II in association with a carrier,diluent and/or excipient.

The present invention also relates to a method for the treatment and/orprophylaxis of obesity and Related Diseases including eating disorders(bulimia, anorexia nervosa, etc.), diabetes, diabetic complications,diabetic retinopathy, sexual/reproductive disorders, depression relatedto obesity, anxiety related to obesity, epileptic seizure, hypertension,cerebral hemorrhage, congestive heart failure, sleeping disorders,atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia,hypertriglycemia, hyperglycemia, hyperlipoproteinemia, substance abuse,drug overdose, compulsive behavior disorders (such as paw licking indog), and addictive behaviors such as for example, gambling, andalcoholism, comprising administering a therapeutically effective amountof a compound of formula I or formula II or a pharmaceuticallyacceptable salt, solvate, enantiomer, racemate, diastereomer or mixtureof diastereomers thereof.

The present invention provides a compound of formula (I) or (II) usefulfor the manufacture of a medicament for the treatment, prevention and/oramelioration of symptoms associated with obesity and Related Diseases.

In another embodiment, the present invention provides a compound offormula I or II or a pharmaceutically acceptable salt, solvate,enantiomer, racemate, diastereomer or mixtures thereof, useful as anappetite suppressant.

In another embodiment, the present invention provides a method ofachieving weight loss while maintaining or minimizing the loss of leanmuscle mass, comprising administering a compound of formula I or II or apharmaceutically acceptable salt, solvate, enantiomer, racemate,diastereomer or mixtures thereof, to a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term “obesity” has its commonly understood meaningsuch as “excessively fat” and includes the clinical designation of beingobese as defined in and by the medical literature and brochures ofsupport or public health organizations. For example, Dorland'sIllustrated Medical Dictionary (29^(th) edition, W.B. Saunders Company,Philadelphia USA.) defines obesity as an increase in bodyweight beyondthe limitation of skeletal and physical requirements, as the result ofan excessive accumulation of fat in the body.” Because the decision ofsuitability for treatment of a patient with compound(s) of the presentinvention to a patient is to be made by a qualified physician or caregiver, the patient is inherently deemed suitable or obese by theadministering caregiver.

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats) and livestock animals.

The preferred patient of treatment, amelioration and/or prevention ofobesity and Related Diseases is human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “ameliorating” “preventing”, “prevention of”, “prophylaxis”,“prophylactic” and “prevent” are used herein interchangeably and referto reducing the severity of the symptoms associated with obesity andRelated Diseases in a patient afflicted with same or reducing thelikelihood that the recipient of a compound of formula I or II willincur or develop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” is synonymous with“effective dose” and means an amount of a compound of formula I or IIthat is sufficient in one or more administrations for preventing,ameliorating or treating a condition, or detrimental effects thereof,herein described, or an amount of a compound of formula I that issufficient for antagonizing the opioid receptors to achieve theobjectives of the invention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “Active Ingredient” as used herein means a compound of formulaI or II or a combination of compounds of formula I or II or acombination of a compound of formula I or II and a co-antagonist of theopioid receptor or a combination of a compound of formula I and/or II inaddition to other effective anti-obesity, weight loss or anti-diabeticagent.

The term “formulation”, as in pharmaceutical formulation, or“pharmaceutical composition” is intended to encompass a productcomprising the Active Ingredient (as defined supra), and the inertingredient(s) that make up the carrier, or other components of the drugas administered, as well as any product which results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical formulations ofthe present invention encompass any effective composition made byadmixing a compound of the present invention and a pharmaceuticalcarrier. The pharmaceutical formulations of the present invention alsoencompass a compound of the formula I or II and a pharmaceuticallyacceptable co-antagonist of opioid receptors useful for the treatmentand/or prevention of obesity or Related Diseases.

The term “Related Diseases” as used herein refers to such symptoms,diseases or conditions caused by, exacerbated by, induced by or adjunctto the condition of being obese. Such diseases, conditions and/orsymptoms include but are not limited to eating disorders (bulimia,anorexia nervosa, etc.), diabetes, diabetic complications, diabeticretinopathy, sexual/reproductive disorders, obesity related depression,obesity related anxiety, epileptic seizure, hypertension, cerebralhemorrhage, congestive heart failure, sleeping disorders,atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia,hypertriglycemia, hyperglycemia, and hyperlipoproteinemia. As usedherein the terms obesity related depression and obesity related anxietyare conditions of depression and anxiety respectively, that aresymptomatic of certain obese patients and possibly brought on by theawareness or self-consciousness of the condition of being obese andpossibly coupled with the real or perceived reaction of acceptance ordisapproval by the certain individual, individuals or the public atlarge. Obesity related depression or anxiety may generally be alleviatedor treated as the condition of being obese is treated and/or preventedby administration of a compound of formula I or II.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “mutual solvent” means a solvent that is used to dissolvesufficiently, two or more components of a reaction or mixture separatelyprior to reaction or mixing, that is a solvent common to more than onereagents or components of a mixture.

The term “nitrogen containing heterocycle” refers to a aromatic ornon-aromatic, monocyclic or bicyclic ring system which is a 4, 5, 6, or7-member ring containing 1, 2 or 3 nitrogen atoms in addition to thecarbon atoms completing the ring size, or a combination of 1 nitrogenatom and 1, or 2 atoms selected from oxygen, and sulfur in addition tothe appropriate number of carbon atoms completing the ring size. Anitrogen containing heterocycle as used here may have 0, 1, 2 or 3double bonds.

The term “C₁-C₈ alkyl” or C₁₋₈ alkyl” refers to and includes all groups,structural isomers and/or homologues of alkyl groups having from 1 to 8carbon atoms. When the term C₁-C₈ alkyl precedes or prefixes anothergroup, the term C₁-C₈ alkyl, only limits the number of carbon atoms inthe alkyl component. For example C₁-C₈ alkyaryl, means an aryl grouphaving a C₁-C₈ alkyl group substituent such that the number of carbonatoms in the group C₁-C₈ alkylaryl is effectively the number of carbonatoms in the aryl group plus the number of carbon atoms in the C₁-C₈alkyl group. Similarly, the term “C₁-C₈ alkylcycloalkyl” refers to acycloalkane group having a C₁-C₈ alkyl substituent, and wherein theentire group C₁-C₈ alkylcycloalkane may itself be a substituent attachedat either the alkyl group or the cycloalkyl group to a substrate. Thedefinition and usage applies equally to other homologues of C₁-C₈ suchas for example, C₁-C₇, C₁-C₆ etc. In general, where necessary a dash (-)has been placed by certain groups that may require it to indicate thepoint of attachement for clarity.

The term “cycloalkane” or “cycloalkyl” means cycloalkanes having from 3to 8 carbon atoms i.e. from cyclopropane to cyclooctane.

The term “hal” or “halo” as used herein refers to a halogen includingfluorine, chlorine, bromine or iodine.

The term “haloalkane” or “haloalkyl” means haloalkanes having from 1 to8 carbon atoms, and from 1 to 3 halogen atoms as allowed by valencyconsiderations. Examples include chloroethyl, trifluoromethyl,2-chloropropyl, etc.

As used herein the terms “alkenyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon double bonds.

As used herein the terms “alkynyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon triple bonds.

As used herein the term “alkoxy” refers to the group “O-alkyl” whereinalkyl is as defined previously.

The term “aryl” as used herein refers to compounds or groups having theHuckel 4n+2 pi electron arrangement and includes for example, phenyl,benzyl, naphthyl, tetrahydronaphthyl, benzothiophene, etc, but excludescarbazoles and other fused tricyclic ring structures.

As used herein the term “aroxy” or “aryloxy” refers to the group“O-aryl” wherein aryl is as defined previously.

As used herein the term “fused bicyclic” means a fused cycloalkane ringsystem wherein each ring has from 4 to 8 carbon atoms (i.e. C₈-C₁₆ fusedbicyclic) and the fused ring system has from 0 to 3 bridgehead carbonatoms. One or both of the fused rings may contain zero or one doublebond. Examples of fused bicyclics include but are not limited tobicyclo[2,2,1]heptyl, bicyclo[2,2,1]heptenyl.

As used herein the term “heterocyclic” or heterocyclyl” or “heterocycle”are used interchangeably and has its usual meaning and includes mono, bior tricyclic or spirocyclic heterocyclic groups unless otherwisespecified. Heterocycles as used herein may contain 1, 2, or 3heteroatoms selected independently from nitrogen, oxygen or sulfur,unless otherwise specified. Examples of heterocylclic groups applicableto the present invention include but are not limited to pyranyl,piparazinyl, pyrrolidinyl, azapanyl, azaflorenyl, isoquinolinyl,indolinyl, thiopheneyl, benzthiopheneyl, oxazolyl, morphorlinyl,thiomorphorlinyl, and piperidinyl. Each of the heterocyclic groups maybe substiututed mono or di or as specified with for example, alkyl,cycloalkyl, aryl, among others as defined. Furthermore, substitution maybe at the 1-position or heteroatom as in piperazine, pyrrolidine or at acarbon atom or both.

As used herein, the term “protecting group” refers to a groups usefulfor masking reactive sites in a molecule to enhance the reactivity ofanother group or allow reaction at another desired site or sitesfollowing which the protecting group may be removed. Protecting groupsare usually used to protect or mask groups including but not limited to—OH, —NH, and —COOH. Suitable protecting groups are known to one ofskill in the art and are described in Protecting groups in OrganicSynthesis, 3^(rd) edition, Greene, T. W.; Wuts, P. G. M. Eds., JohnWiley and Sons, New York, 1999.

As used herein, the term “solvate” is a form of the compound of theinvention wherein a crystal or crystals of a compound of the inventionhave been formed from a stoichiometric or non-stoichiometric amount ofthe compound of formula I or II and a solvent. Typical solvatingsolvents include for example, water, methanol, ethanol, acetone anddimethylformamide.

In those instances where a compound of the invention possesses acidic orbasic functional groups, various salts may be formed which are morewater soluble and/or more physiologically suitable than the parentcompound. Representative pharmaceutically acceptable salts, include butare not limited to, the alkali and alkaline earth salts such as lithium,sodium, potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion-exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate,clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate,fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate,hydroiodide, isothionate, lactate, lactobionate, laurate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate,phosphate, polygalacturonate, salicylate, stearate, subacetate,succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate. Preferred salts for thepurpose of the invention include the hydrochloride salt, thehydrobromidse salt, the bisulfate salt, the methane sulfonic acid salt,the p-toluenesulfonic acid salt, bitartrate, the acetate and the citratesalt.

A compound of the invention as illustrated by formula I or II may occuras any one of its positional isomers, stereochemical isomers orregio-isomers, all of which are objects of the invention. Certaincompounds of the invention may possess one or more chiral centers, andthus, may exist in optically active forms. Likewise, when the compoundscontain an alkenyl or alkenylene group, there exist the possibility ofcis- and trans-isomeric forms of the compounds. The R- and S-isomers andmixtures thereof, including racemic mixtures as well as mixtures ofenantiomers or cis- and trans-isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereospecific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods. For example, a racemicmixture may be reacted with a single enantiomer of some other compoundi.e. a chiral resolving agent. This changes the racemic form into amixture of stereoisomers and diastereomers, because they have differentmelting points, different boiling points, and different solubilities andcan be separated by conventional means, such as crystallization.

PCT international application WO 02/078693 A2 published Oct. 10, 2002discloses compounds of the formula

wherein R₁, R₂, R₃, R₄ and X are as described therein, as antagonists ofthe 5-HT₆ receptor for the treatment of disorders including cognitivedisorders, age related disorders, mood disorders, psychosis, etc. Thecompounds of the present invention however, are useful for the treatmentand/or prevention of obesity and Related Diseases. The compounds of thepresent invention have also shown inhibition of orexigenic effects, andare thus useful as appetite suppressants either as a single therapy oras combination therapy in conjunction with exercise and other effectiveappetite suppressing or weight loss medications.

The efficacy of compounds of the present invention have been shown bytheir activity in several biological models including a scintillationproximity assay (SPA GTP-gamma binding assay), an opioid receptorex-vivo binding assay, a rat obesity in-vivo assay and an indirectcalorimetry assay that measurers energy balance and respiratoryquotient. In these models, sample compounds of the present inventionperformed better than or about equal to reference compounds. The primaryreference compound is a highly potent former clinical trial candidate LY255582 disclosed in U.S. Pat. No. 4,891,379, which development wasdiscontinued for lack of satisfactory human oral bioavailablility. Oraladministration of the opioid receptor antagonist LY255582 has been shownto produce robust reductions in food intake following acute and chronictreatment in rats. Moreover, chronic treatment with LY255582 produced asustained negative energy balance leading to a decrease in total bodymass in dietary induced obese rats fed a high fat diet. Interestinglysample compounds of the present invention have been found to producesimilar or better beneficial effects compared to LY255582. Alsointeresting is the secondary observation that tested sample compounds ofthe present invention performed better in our tests when compared withNaltrexone HCl®.

Preferred Embodiments of the Invention

A compound of formula I preferably exists as the free base or apharmaceutically acceptable salt. More preferred is the hydrochloridesalt, the bisulfate salt, mesylate or the oxalic acid salt of thecompound of formula I or II.

Preferred embodiments of the compound of formula I include thesubstructures Ia, Ib and Ic as shown below:

provided that R¹ and R² are not simultaneously hydrogen and providedthat when v is 2, and R³ and R^(3′) are both hydrogen or methyl, and theA ring is phenyl, the group —NR¹R² is not equal to —NHCH₂Ph.For the Groups R¹ and R²

Preferred R¹ and R² groups are independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, phenyl, naphthylbenzothiophene, and isopropyl provided that R¹ and R² are notsimultaneously hydrogen, and provided that when v is 2, and R³ andR^(3′) are both hydrogen or CH₃, and both A and B rings are phenyl, thenthe group —NR¹R² is not equal to —NHCH₂Phenyl; and further provided thatwhen one of R¹ or R² is —CH₂CH₂-optionally substituted phenyl or—CH₂CH₂-optionally substituted naphthyl, or —CH₂CH₂-optionallysubstituted 5 or 6 member monocyclic heterocyclic aromatic, and v is 1,and both A and B rings are phenyl, then R⁶ and R⁷ are not simultaneouslyhydrogen;

Also preferred are R¹ and R² groups independently selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, phenyl,

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or —C₁-C₄ alkylheterocycle; or combine with a groupselected from C₁-C₈ alkyl, halogen, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl,C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈heterocycle or C₁-C₄ alkyl heterocycle to form a substituted orunsubstituted bicycle or tricycle, and wherein n is preferably 1, 2, or3; and provided that when v is 2, and R³ and R^(3′) are both hydrogen orCH₃, and both A and B rings are phenyl, then the group —NR¹R² is notequal to —NHCH₂Phenyl; and further provided that when one of R¹ or R² is—CH₂CH₂-optionally substituted phenyl or —CH₂CH₂-optionally substitutednaphthyl, or —CH₂CH₂-optionally substituted 5 or 6 member monocyclicheterocyclic aromatic, and v is 1, and both A and B rings are phenyl,then R⁶ and R⁷ are not simultaneously hydrogen; The broken (dashed) bondindicates the point of attachment tot eh substrate.

Also preferred are R¹ and R² groups that combine with each other or with1 or 2 atoms adjacent to the nitrogen atom to form a group selected fromthe group consisting of

each of which is optionally substituted with a group selected from thegroup consisting of halogen, amino, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, —C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or —C₁-C₄ alkylheterocycle.Preferred R³ and R^(3′) Groups

A preferred R³ is hydrogen. A preferred R^(3′) group is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl andbenzyl.

Preferred R⁴ Groups

A preferred R⁴ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, —C₁-C₅ alkylamino,—N(C₁-C₅ alkyl)₂, —NHC₁-C₅ alkyl, —C₁-C₅ alkyl N(C₁-C₅ alkyl)₂, —C₁-C₅alkylNHC₁-C₅ alkyl, phenyl, —C₁-C₅ alkylphenyl, —C₁-C₅ alkylcycloalkyl,and C₁-C₅ thioalkyl. More preferred is a R⁴ group selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, chloro, fluoro,trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl, and benzyl. Mostpreferred is an R⁴ group selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, fluoro, chloro, trifluoromethyl, methoxy,ethoxy, propoxy, isopropoxy, and benzyl.

Though the groups R⁴ and a R⁵ may exist as multiple substituents ontheir respective ring substrates, a preferred embodiment of theinvention involves compounds wherein each of R⁴, and R⁵ areindependently singly or doubly substituted on their respective ringsubstrates.

Preferred R⁵ Groups

A preferred R⁵ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, —C₁-C₅ alkylamino,—N(C₁-C₅ alkyl)₂, —NHC₁-C₅ alkyl, —C₁-C₅ alkylN(C₁-C₅ alkyl)₂, —C₁-C₅alkylNHC₁-C₅ alkyl, phenyl, —C₁-C₅ alkylphenyl, —C₁-C₅ alkylcycloalkyl,and C₁-C₅ thioalkyl. More preferred is an R⁵ group selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, chloro, fluoro,trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl, and benzyl. A mostpreferred R⁵ group is selected from the group consisting of hydrogen,methyl, ethyl, isopopropyl, fluoro, chloro, trifluoromethyl, methoxy,ethoxy, trifluoromethoxy, and benzyl.

Preferred R⁶ and R⁷ Groups

Preferred are R⁶ and R⁷ groups independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, isopropyl, phenyland benzyl, provided that when one of R¹ or R² is —CH₂CH₂-optionallysubstituted phenyl or —CH₂CH₂-optionally substituted naphthyl, or—CH₂CH₂-optionally substituted 5 or 6 member monocyclic heterocyclicaromatic, and v is 1, and both A and B rings are phenyl, then R⁶ and R⁷are not simultaneously hydrogen.

Also preferred are compounds of formula I wherein R⁶ and R⁷ mayindependently combine with each other, and with the nitrogen atom towhich they are attached or with 1, or 2 atoms adjacent to the nitrogenatom to form a 4, 5, 6, or 7-membered nitrogen containing heterocyclewhich nitrogen containing heterocycle may optionally have substituentsselected from the group consisting of oxo, amino, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, phenyl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl,—CO(O)C₁-C₈ alkyl, hydroxy, C₁-C₈ alkoxy, halo, and haloalkyl.

Most preferred are compounds of the invention wherein R⁶ and R⁷ are bothhydrogen except as provided for previously.

Preferred E Group

A most preferred E group is an oxygen atom (O).

Preferred A-Ring

A preferred A-ring is a phenyl ring or a pyridine ring.

Preferred B-Ring

A preferred B-ring is a phenyl ring, a pyrazine ring, a pyrimidine ringor a pyridine ring. Most preferred B ring is a phenyl, pyrazine orpyridine ring.

Preferred Values for v, n and m

A preferred value for v is 1, or 2.

A preferred value for n is 1, 2 or 3.

A preferred value for m is 1 or 2.

For the Groups R^(1′) and R^(2′)

Preferred R^(1′) and R^(2′) groups are independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, pentyl, andisopropyl provided that R^(1′) and R^(2′) are not simultaneouslyhydrogen, and provided that when v is 2, and R^(3a) and R^(3b) are bothhydrogen or CH₃, and both A′ and B′ rings are phenyl, then the group—NR^(1′)R^(2′) is not equal to —NHCH₂Phenyl; and further provided thatwhen one of R^(1′) or R^(2′) is —CH₂CH₂-optionally substituted phenyl or—CH₂CH₂-optionally substituted naphthyl, or —CH₂CH₂-optionallysubstituted 5 or 6 member monocyclic heterocyclic aromatic, and v is 1,and both A′ and B′ rings are phenyl, then R^(6′) and R^(7′) are notsimultaneously hydrogen; Also preferred are R^(1′) and R^(2′) groupsindependently selected from the group consisting of hydrogen, methyl,ethyl, propyl, isopropyl, phenyl,

each of which is optionally substituted with a group selected fromhalogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl, C₁-C₈alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈ heterocycle orC₁-C₄ alkyl heterocycle; or combine with a group selected from C₁-C₈alkyl, halogen, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl, C₁-C₈ alkylamino,phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈ heterocycle or C₁-C₄ alkylheterocycle to form a substituted or unsubstituted bicycle or tricycle,and wherein n is preferably 1, 2 or 3; and provided that when v is 2,and R^(3a) and R^(3b) are both hydrogen or CH₃, and both A′ and B′ ringsare phenyl, then the group —NR^(1′)R^(2′) is not equal to —NHCH₂Phenyl;and further provided that when one of R^(1′) or R^(2′) is—CH₂CH₂-optionally substituted phenyl or —CH₂CH₂-optionally substitutednaphthyl, or —CH₂CH₂-optionally substituted 5 or 6 member monocyclicheterocyclic aromatic, and v is 1, and both A′ and B′ rings are phenyl,then R^(6′) and R^(7′) are not simultaneously hydrogen.

Also preferred are R^(1′) and R^(2′) groups which combine with eachother or with 1 or 2 atoms adjacent to the nitrogen atom to form a groupselected from the group consisting of:

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkylheterocycle.Preferred R^(3a) and R^(3b) Groups

A preferred R^(3a) is hydrogen. A preferred R^(3b) group is selectedfrom hydrogen, methyl, ethyl, propyl, isopropyl, phenyl and benzyl.

Preferred R^(4′) Groups

A preferred R^(4′) group is selected from the group consisting ofhydrogen, halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, —C₁-C₅alkylamino, —N(C₁-C₅ alkyl)₂, —NHC₁-C₅ alkyl, —C₁-C₅ alkylN(C₁-C₅alkyl)₂, —C₁-C₅ alkylNHC₁-C₅ alkyl, phenyl, —C₁-C₅ alkylphenyl, —C₁-C₅alkylcycloalkyl, and C₁-C₅ thioalkyl. More preferred is a R^(4′) groupselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, thiomethyl,phenyl, and benzyl. A most preferred R^(4′) group is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro,trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, and benzyl.

Though the groups R^(4′) and R^(5′) may exist as multiple substituentson their respective ring substrates, a preferred embodiment of theinvention involves compounds wherein each of R^(4′), and R^(5′) aresingly or doubly substituted on their respective ring substrates.

Preferred R^(5′) Groups

A preferred R^(5′) group is selected from the group consisting ofhydrogen, halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, —C₁-C₅alkylamino, —N(C₁-C₅ alkyl)₂, —NHC₁-C₅ alkyl, —C₁-C₅ alkylN(C₁-C₅alkyl)₂, —C₁-C₅ alkylNHC₁-C₅ alkyl, phenyl, —C₁-C₅ alkylphenyl, —C₁-C₅alkylcycloalkyl, and C₁-C₅ thioalkyl. More preferred is an R^(5′) groupselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy,ethoxy, thiomethyl, phenyl, and benzyl. A most preferred R^(5′) group isselected from the group consisting of hydrogen, methyl, ethyl,isopopropyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, and benzyl.

Preferred R^(6′) and R^(7′) Groups

Preferred are R^(6′) and R^(7′) groups independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, pentyl, isopropyl,phenyl and benzyl provided that when one of R^(1′) or R^(2′) is—CH₂CH₂-optionally substituted phenyl or —CH₂CH₂-optionally substitutednaphthyl, or —CH₂CH₂-optionally substituted 5 or 6 member monocyclicheterocyclic aromatic, and v is 1, and both A′ and B′ rings are phenyl,then R^(6′) and R^(7′) are not simultaneously hydrogen.

Also preferred are compounds of formula II wherein R^(6′) and R^(7′) mayindependently combine with each other, and with the nitrogen atom towhich they are attached or with 1, or 2 atoms adjacent to the nitrogenatom to form a 4, 5, 6, or 7-membered nitrogen containing heterocyclewhich nitrogen containing heterocycle may optionally have substituentsselected from the group consisting of oxo, amino, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, phenyl, —C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl,—CO(O)C₁-C₈ alkyl, hydroxy, C₁-C₈ alkoxy, halo, and haloalkyl.

Most preferred are compounds of formula II wherein R^(6′) and R^(7′) areboth hydrogen provided that when one of R^(1′) or R^(2′) is—CH₂CH₂-optionally substituted phenyl or —CH₂CH₂-optionally substitutednaphthyl, or —CH₂CH₂-optionally substituted 5 or 6 member monocyclicheterocyclic aromatic, and v is 1, and both A′ and B′ rings are phenyl,then R^(6′) and R^(7′) are not simultaneously hydrogen.

Preferred E′ Group

A most preferred E′ group is an oxygen atom (O).

Preferred A′-Ring

A preferred A′-ring is a phenyl ring or a pyridine ring.

Preferred B′-Ring

A preferred B′-ring is a phenyl ring, a pyrazine ring, a pyrimidine ringor a pyridine ring. Most preferred B′ ring is a phenyl, pyrazine orpyridine ring.

A preferred compound according to the present invention is a compoundselected from the group consisting of:

-   6-[4-(2-Benzylamino-ethyl)-phenoxy]-nicotinamide.-   6-{4-[2-(Benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[Benzyl-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(Benzyl-hexyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-heptyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[Benzyl-(5-methyl-hexyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-{Benzyl-[2-(3-chloro-phenyl)-ethyl]-amino}-ethyl)-phenoxy]-nicotinamide,-   6-(4-{2-[Benzyl-(3-cyclohexyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-o-tolyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(Benzyl-pentyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[Benzyl-(3-cyclopentyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-{Benzyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Dibenzylamino-ethyl)-phenoxy]-nicotinamide,-   6-(4-{2-[Benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-oxo-3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-cyclohexyl-3-oxo-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-hydroxy-3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[Benzyl-(3-cyclohexyl-3-hydroxy-propyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(3-Phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(2-Phenethylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Hexylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Heptylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Pentylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(5-Methyl-hexylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[2-(3-Chloro-phenyl)-ethylamino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(3-Cyclopentyl-propylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Cyclohexyl-propylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[2-(3-Fluoro-phenyl)-ethylamino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(3-o-Tolyl-propylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Thiophen-2-yl-propylamino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(2-Amino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(2-Methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Chloro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3,4-Dichloro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Trifluoromethyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Cyano-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Methyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3,5-Bis-trifluoromethyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2,6-Difluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide-   6-{4-[2-(3,5-Difluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Acetylamino-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Trifluoromethyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Methyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Chloro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Phenoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Trifluoromethyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Oxo-2,3-dihydro-1H-isoindol-1-ylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Trifluoromethoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Trifluoromethoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(Thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Furan-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4(2-Octylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Cyclohexylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(2-Propylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Butylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Isopropylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Isobutylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(3-Methyl-butylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(Pyridin-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Pyridin-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(3-Methyl-thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(5-Methyl-thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Thiophen-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-Ethylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(4-Hydroxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Hydroxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Phenyl-prop-2-ynylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(Furan-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Benzofuran-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(5-Ethyl-furan-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(5-Chloro-thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Thiazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(2-Methyl-1H-imidazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(3,5-Di-tert-butyl-4-hydroxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Phenoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Chloro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Cyano-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Methyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(1H-Imidazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Pyridin-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(2-Phenoxy-ethylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Fluoro-4-hydroxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(2-Butyl-1H-imidazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Benzo[b]thiophen-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(3-Phenyl-1H-pyrazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-Allylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(4-Imidazol-1-yl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(3-Methyl-benzo[b]thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(4-Methyl-pent-2-enylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Trifluoromethoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(2-Piperidin-1-yl-thiazol-5-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(4-Cyclohexyl-butylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Cyclohexyl-ethylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Chloro-6-fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Cyclopropylmethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(Naphthalen-1-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Naphthalen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Quinolin-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(2,6-Dichloro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Indan-1-ylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Hydroxy-5-methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Bromo-4-fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Fluoro-2-trifluoromethyl-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Chloro-4-fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(2-Cyclooctylamino-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(2-Phenoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Cyclobutylmethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Cycloheptylmethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(2-Morpholin-4-yl-thiazol-5-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(2,4-Dichloro-thiazol-5-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(2-Chloro-thiazol-5-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(Cyclopentylmethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[(3,5-Dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(5-Methyl-isoxazol-3-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(3-Phenyl-isoxazol-5-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-{[3-(4-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-amino}-ethyl)-phenoxy]-nicotinamide,-   6-(4-{2-[(5-p-Tolyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide,-   6-{4-[2-(1-Phenyl-ethylamino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(3-Benzylamino-propyl)-phenoxy]-nicotinamide,-   6-{4-[3-(Benzyl-pentyl-amino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[3-(Benzyl-phenethyl-amino)-propyl]-phenoxy}-nicotinamide,-   6-(4-{3-[Benzyl-(3-cyclopentyl-propyl)-amino]-propyl}-phenoxy)-nicotinamide,-   6-[4-(3-{Benzyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-propyl)-phenoxy]-nicotinamide,-   6-[4-(3-Pentylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(3-Phenethylamino-propyl)-phenoxy]-nicotinamide,-   6-{4-[3-(3-Cyclopentyl-propylamino)-propyl]-phenoxy}-nicotinamide,-   6-(4-{3-[2-(3-Fluoro-phenyl)-ethylamino]-propyl}-phenoxy)-nicotinamide,-   (R)-6-[4-(2-Benzylamino-propyl)-phenoxy]-nicotinamide,-   (R)-6-[4-(2-Dibenzylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Benzylamino-2-methyl-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Methyl-2-pentylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Methyl-2-phenethylamino-propyl)-phenoxy]-nicotinamide,-   6-(4-{2-[2-(3-Fluoro-phenyl)-ethylamino]-2-methyl-propyl}-phenoxy)-nicotinamide,-   6-{4-[2-(3-Cyclopentyl-propylamino)-2-methyl-propyl]-phenoxy}-nicotinamide,-   6-[4-(3-Benzylamino-butyl)-phenoxy]-nicotinamide,-   6-[4-(3-Pentylamino-butyl)-phenoxy]-nicotinamide,-   6-[4-(3-Propylamino-butyl)-phenoxy]-nicotinamide,-   6-[4-(3-Methylamino-butyl)-phenoxy]-nicotinamide,-   6-[4-(3-Phenethylamino-butyl)-phenoxy]-nicotinamide,-   6-(4-{3-[2-(3-Fluoro-phenyl)-ethylamino]-butyl}-phenoxy)-nicotinamide,-   6-(4-{3-[2-(3-Chloro-phenyl)-ethylamino]-butyl}-phenoxy)-nicotinamide,-   6-(4-{3-[(Furan-2-ylmethyl)-amino]-butyl}-phenoxy)-nicotinamide,-   6-{4-[3-(2-Thiophen-2-yl-ethylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(Cyclopropylmethyl-amino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(3-Trifluoromethyl-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(4-Fluoro-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(3-Fluoro-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-[4-(3-Allylamino-butyl)-phenoxy]-nicotinamide,-   6-{4-[3-(4-Chloro-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(4-Methoxy-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(4-Trifluoromethyl-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(4-Trifluoromethoxy-benzylamino)-butyl]-phenoxy}-nicotinamide,-   6-{4-[3-(3-Trifluoromethoxy-benzylamino)-butyl]-phenoxy}-nicotinamide,-   (1R)-6-{4-[3-(1-Phenyl-ethylamino)-butyl]-phenoxy}-nicotinamide,-   (1S)-6-{4-[3-(1-Phenyl-ethylamino)-butyl]-phenoxy}-nicotinamide,-   6-[4-(2-Benzylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Pentylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Propylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Methylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Phenethylamino-propyl)-phenoxy]-nicotinamide,-   6-(4-{2-[2-(3-Fluoro-phenyl)-ethylamino]-propyl}-phenoxy)-nicotinamide,-   6-(4-{2-[2-(3-Chloro-phenyl)-ethylamino]-propyl}-phenoxy)-nicotinamide,-   6-(4-{2-[(Furan-2-ylmethyl)-amino]-propyl}-phenoxy)-nicotinamide,-   6-{4-[2-(2-Thiophen-2-yl-ethylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Cyclopropylmethyl-amino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Trifluoromethyl-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Fluoro-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Fluoro-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-[4-(2-Allylamino-propyl)-phenoxy]-nicotinamide,-   6-{4-[2-(4-Chloro-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Trifluoromethyl-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Methoxy-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Trifluoromethoxy-benzylamino)-propyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Trifluoromethoxy-benzylamino)-propyl]-phenoxy}-nicotinamide,-   (1S)-6-{4-[2-(1-Phenyl-ethylamino)-propyl]-phenoxy}-nicotinamide,-   (1R)-6-{4-[2-(1-Phenyl -ethylamino)-propyl]-phenoxy}-nicotinamide,-   6-[4-(2-Benzylamino-1-methyl-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(Benzyl-pentyl-amino)-1-methyl-ethyl]-phenoxy}-nicotinamide,-   6-[4-(1-Methyl-2-pentylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Benzylamino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(Cyclohexylmethyl-amino)-1,1-dimethyl-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(2-Chloro-benzylamino)-1,1-dimethyl-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Fluoro-benzylamino)-1,1-dimethyl-ethyl]-phenoxy}-nicotinamide,-   6-[4-(3-Phenylamino-propyl)-phenoxy]-nicotinamide,-   6-[4-(2-Dimethylamino-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-nicotinamide,-   6-[4-(2-Morpholin-1-yl-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Benzoyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3-Methyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(3,5-Dimethyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(4-Phenyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide,-   6-(4-{2-[3-Fluoro-phenyl)-piperidin-1-yl]-ethyl}-phenoxy)-nicotinamide,-   6-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-nicotinamide,-   6-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-ethyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-propyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-butyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-cyclopropylmethylamino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-isobutyl-amino)-ethyl]-phenoxy}-nicotinamide,-   6-{4-[2-(Benzyl-(3-methyl-butyl)-amino)-ethyl]-phenoxy}-nicotinamide,-   6-[4-(2-Benzoylamino-ethyl)-phenoxy]-nicotinamide,-   4-[4-(2-Benzylamino-ethyl)-phenoxy]-2-fluoro-benzamide,-   2-[4-(2-Benzylamino-ethyl)-phenoxy]-4-fluoro-benzamide,-   4-[4-(2-Benzylamino-ethyl)-phenoxy]-2-chloro-benzamide,-   6-[4-(2-Benzylamino-ethyl)-2-methyl-phenoxy]-nicotinamide,-   6-[2-Methyl-4-(phenethylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Fluoro-4-(phenethylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Ethoxy-4-(phenethylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Chloro-4-(phenethylamino-methyl)-phenoxy]nicotinamide,-   6-[3-Chloro-4-(phenethylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Methyl-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Fluoro-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Chloro-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide,-   6-[2-Ethoxy-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide,-   6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-methyl-phenoxy}-nicotinamide,-   6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-fluoro-phenoxy}-nicotinamide,-   6-{2-Chloro-4-[2-Cyclopentyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-ethoxy-phenoxy}-nicotinamide,-   6-{2-Methyl-4-[2-thiophen-2-yl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-nicotinamide,-   6-{2-Methyl-4-[(2-o-tolyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-methyl-phenoxy}-nicotinamide,-   6-(4-{[2-(3-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-nicotinamide,-   6-(4-Butylaminomethyl-2-methyl-phenoxy)-nicotinamide,-   6-(2-Methyl-4-{[methyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinamide,-   6-{2-Methyl-4-[(methyl-phenethyl-amino)-methyl]-phenoxy}-nicotinamide,-   3-Fluoro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide,-   3-Chloro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide,-   2-Chloro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide,-   3-Fluoro-4-{2-methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide,-   4-(4-Benzylamino-phenoxy)-benzamide,-   4-(4-Phenethylamino-phenoxy)-benzamide,-   6-[4-(Benzylamino-methyl)-phenoxy]-nicotinamide,-   6-(4-Allylaminomethyl-phenoxy)-nicotinamide,-   6-{4-[(4-Methoxy-benzylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3-Trifluoromethyl-benzylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Thiophen-2-yl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3-Fluoro-benzylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[(Furan-2-ylmethyl)-amino]-methyl}-phenoxy)-nicotinamide,-   6-(4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(4-Trifluoromethoxy-benzylamino)-methyl]-phenoxy}-nicotinamide,-   6-[4-(Phenethylamino-methyl)-phenoxy]-nicotinamide,-   6-(4-{[2-(3-Chloro-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-(4-{[2-(4-Sulfamoyl-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(3-Phenyl-propylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3,3-Diphenyl-propylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3,3-Dimethyl-butylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[2-(2-Methoxy-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(2-Phenylamino-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Phenyl-propylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Pyridin-2-yl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[2-(2-Chloro-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(2-Pyridin-3-yl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2,2-Diphenyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Cyclohexyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Methylsulfanyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(6-Hydroxy-hexylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-Decylaminomethyl-phenoxy)-nicotinamide,-   6-{4-[(2-Ethyl-hexylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[(Tetrahydro-furan-2-ylmethyl)-amino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-(4-{[2-(1H-Imidazol-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-(4-{[3-(2-Methyl-piperidin-1-yl)-propylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(2-Diisopropylamino-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-{4-[(2-Cyclohex-1-enyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-Pentylaminomethyl-phenoxy)-nicotinamide,-   4-{4-[(4-Trifluoromethoxy-benzylamino)-methyl]-phenoxy}-benzamide,-   4-(4-{[2-(3-Chloro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-{4-[(4-Trifluoromethyl-benzylamino)-methyl]-phenoxy}-benzamide,-   4-{4-[(4-Fluoro-benzylamino)-methyl]-phenoxy}-benzamide,-   4-(4-Pentylaminomethyl-phenoxy)-benzamide,-   4-{4-[(2-Phenyl-propylamino)-methyl]-phenoxy}-benzamide,-   4-(4-{[2-(2-Chloro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(2,4-Dichloro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(2-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(2,5-Dimethoxy-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-(4-{[2-(2,6-Dichloro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   4-{4-[(2-o-Tolyl-ethylamino)-methyl]-phenoxy}-benzamide,-   4-{4-[(2,2-Diphenyl-ethylamino)-methyl]-phenoxy}-benzamide,-   4-[4-(3-Phenyl-propylamino)-phenoxy]-benzamide,-   4-{4-[(2-Cyclopentyl-ethylamino)-methyl]-phenoxy}-benzamide,-   4-{4-[(2,6-Dichloro-benzylamino)-methyl]-phenoxy}-benzamide,-   4-(4-{[(Furan-2-ylmethyl)-amino]-methyl}-phenoxy)-benzamide,-   6-(4-{[2-(3,4-Dichloro-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-(4-{[2-(2-Ethoxy-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   6-{4-[(2-o-Tolyl-ethylamino)-methyl]-phenoxy}-nicotinamide,-   6-(4-{[2-(2-Phenoxy-phenyl)-ethylamino)-methyl}-phenoxy)-nicotinamide,-   6-[4-((2-Thiophenyl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinamide,-   6-[4-((3-Methyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinamide    methanesulfonate salt,-   6-[4-((3-Dimethyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinamide,-   6-[4-(Butylamino-methyl)-2-ethoxyphenoxy]nicotinamide,-   6-[4-((2-Phenyl-ethyamino)-methyl)-2,5-dimethylphenoxy]nicotinamide,-   6-[4-((2-Cyclopentyl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinamide    metanosulfonate salt,-   6-[4-((3-Methyl-butylamino)-methyl)-2,5-dimethylphenoxy]nicotinamide-   6-(4-Iodo-phenoxy)-nicotinamide,-   (±)-6-(4-Piperidin-3-yl-phenoxy)-nicotinamide,-   (±)-6-[4-(1-Benzyl-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-[4-(1-Cyclohexylmethyl-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-[4-(1-Methyl-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-[4-(1-(3-Fluoro-benzyl)-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-[4-(1-(2-Fluoro-benzyl)-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-[4-(1-Hexyl-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-{4-[1-(3-Methyl-butyl)-piperidin-3-yl]-phenoxy}-nicotinamide,-   (±)-6-[4-(1-Phenethyl-piperidin-3-yl)-phenoxy]-nicotinamide,-   (±)-6-{4-[1-(2-Cyclohexyl-ethyl)-piperidin-3-yl]-phenoxy}-nicotinamide,-   6-[4-(4-Benzyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4-Phenethyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4-Cyclopentyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-{4-[4-(1-Phenyl-ethyl)-piperazin-1-ylmethyl]-phenoxy}-nicotinamide,-   6-[4-(4-Benzhydryl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-{4-[4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl]-phenoxy}-nicotinamide,-   6-[4-(4-Phenyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4-Cyclohexyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4-Isopropyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide,-   (3R)-6-{4-[(1-Benzyl-pyrrolidin-3-ylamino)-methyl]-phenoxy}-nicotinamide,-   (3S)-6-{4-[(1-Benzyl-pyrrolidin-3-ylamino)-methyl]-phenoxy}-nicotinamide,-   (±)-6-[4-(2-Phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(2-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,    hydrochloric acid salt,-   (±)-6-[4-(3-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4-Phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(3-Phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(4-Phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(4,4-Diphenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(3,3-Diphenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-[4-(2,2-Diphenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,-   6-(4-Piperidin-1-ylmethyl-phenoxy)-nicotinamide,-   (±)-6-[4-(1,2,4,4a,9,9a-Hexahydro-3-aza-fluoren-3-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-{4-[3-(2-Chloro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide,-   (±)-6-{4-[3-(3-Chloro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide,-   (±)-6-{4-[3-(3-Trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide,-   (±)-6-[4-(3-Methyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(3-Phenethyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(3-Phenpropyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(3-Benzyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[4-(3-Phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-{4-[3-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide,    hydrochloric acid salt,-   (±)-6-{4-[3-(2-Fluoro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide,    hydrochloric acid salt,-   (±)-6-[4-(3-Cyclohexyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,    hydrochloric acid salt,-   (±)-6-[2-Methyl-4-(3-phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide,    hydrochloric acid salt,-   (±)-6-[2-Methyl-4-(3-phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide,    hydrochloric acid salt,-   (±)-6-[2-Methyl-4-(4-phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-1-{6-[2-Methyl-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-pyridin-3-yl}-ethanone,-   (±)-5-(1,1-Difluoro-ethyl)-2-[2-methyl-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-pyridine    hydrochloric acid salt,-   (±)-6-[2-Fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide,-   (±)-6-[2-Chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide-   6-(3-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide,-   6-(3-Benzyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotinamide,-   6-[4-(Phenethylaminomethyl)phenoxy]nicotinamide,-   {2-[4-(5-Aminomethylpyridin-2-yloxy)phenyl]ethyl}benzylamine,-   5-[4-(Phenethylaminomethyl)phenoxy]pyridine-2-carboxyamide,-   2-[4-(2-Benzylaminoethyl)phenoxy]nicotinamide,-   6-[4-(2-Benzylaminoethyl)phenoxy]pyridine-2-carboxamide,-   2-[4-(2-Benzylaminoethyl)phenoxy]isonicotinamide,-   N-Methyl-{6-[4-(phenethylaminomethyl)phenoxy]nicotinamide,-   5-[4-(Phenethylaminomethyl)phenoxy]pyrazine-2-carboxamide,-   5-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide,-   5-{4-[(3-Methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-(4-{[2-(3-Trifluoromethylphenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide    methanesulfonate,-   5-{4-[(2-Thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{2-Methyl-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{2-Methoxy-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{4-[(2-Cyclopentylethylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{4-[(2-Cyclopentylethylamino)methyl]-2-methylphenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{4-[(2-Cyclopentylethylamino)methyl]-2-methoxyphenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-(4-{[(Benzo[b]thiophen-3-ylmethyl)amino]methyl}phenoxy)pyridine-2-carboxamide    methanesulfonate,-   5-(4-{[2-(4-Methoxyphenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide    methanesulfonate,-   5-(4-{[2-(3-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide    methanesulfonate,-   5-(4-{[2-(2-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide    methanesulfonate,-   5-{2-Fluoro-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide    methanesulfonate,-   5-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide    methanesulfonate,-   5-(2-Fluoro-4-pentylaminomethylphenoxy)pyridine-2-carboxamide-   5-{2-Fluoro-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{2-Fluoro-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{2-Fluoro-4-[(2-m-tolylethylamino)methyl]phenoxy{pyridine-2-carboxamide,-   5-(2-Fluoro-4-{[2-(4-fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide,-   5-{2-Chloro-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-(2-Chloro-4-(pentylaminomethyl)phenoxy)pyridine-2-carboxamide,-   5-{2-Chloro-4-[(2-thiophen-2-y]ethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{2-Chloro-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   6-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide,-   5-(2-Fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide,-   5-{2-Fluoro-4-[(2-o-tolylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{4-[(2-Naphthalen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{4-[(2-Naphthalen-1-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   5-{4-[(2-Benzo[b]thiophen-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide,-   6-(2-Methoxy-4-pentylaminomethylphenoxy)nicotinamide,-   6-{2-Methoxy-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}nicotinamide,-   6-{2-Methoxy-4-[(2-o-tolylethylamino)methyl]phenoxy}nicotinamide,-   6-{2-Methoxy-4-[(2-o-tolylethylamino)methyl]phenoxy}nicotinamide,-   6-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide,-   6-{2-Methoxy-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}nicotinamide,-   6-(4-Butylaminomethyl-2-methoxyphenoxy)nicotinamide,-   6-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide,-   6-{2-Methoxy-4-[(2-morpiholin-4-ylethylamino)methyl]phenoxy}nicotinamide,-   6-{4-[(2-Ethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide,-   6-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide,-   6-(4-{[2-(2-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide,-   6-(4-Hexylaminomethyl-2-methoxyphenoxy)nicotinamide,-   6-{2-Methoxy-4-[(4-methylpentylamino)methyl]phenoxy}nicotinamide    methanesulfonate,-   6-{2-Methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamide    methanesulfonate,-   5-(2-Methyl-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide,-   5-{4-[(3,3-Dimethylbutylamino)methyl]-2-methylphenoxy}pyrazine-2-carboxamide,-   5-{4-[(3-Methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide,-   5-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide,-   5-{4-[(3,3-Dimethylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide,-   6-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide    methanesulfonate,-   6-(4-Hexylaminomethyl-2-methoxyphenoxy)nicotinamide    methanesulfonate,-   6-(2-Methoxy-4-pentylaminomethylphenoxy)nicotinamide    methanesulfonate,-   6-(4-Butylaminomethyl-2-methoxyphenoxy)nicotinamide    methanesulfonate,-   6-{2-Methoxy-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}nicotinamide    methanesulfonate,-   6-{4-[(2-Ethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide    methanesulfonate,-   6-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide    methanesulfonate,-   6-f2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide    methanesulfonate,-   6-(2-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide,-   6-[2-(3-Methylbutyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide,-   6-[2-(3-Methylpentyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide,-   (±)-6-{4-[2-(2-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide,-   (±)-(cis)-6-{4-[2-(3-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide,-   (±)-(trans)-6-{4-[2-(3-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide,-   (±)-6-{4-[2-((trans)-4-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide,-   (±)-6-{4-[2-((trans)-2-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide,-   4-[5-(Phenethylamino-methyl)-pyridin-2-yloxy]-benzamide    dihydrochloride    4-{5-[(3-Trifluoromethyl-benzylamino)-methyl]-pyridin-2-yloxy}-benzamide    4-{5-[(3-Phenyl-propylamino)-methyl]-pyridin-2-yloxy}-benzamide-   4-{5-[(4-Fluoro-benzylamino)-methyl]-pyridin-2-yloxy}-benzamide    4-[5-(Isobutylamino-methyl)-pyridin-2-yloxy]-benzamide    4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamide-   4-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide-   4-(5-{[2-(2-Methoxy-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide    4-(5-{[2-(2-Chloro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide    4-[5-(3-Phenyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxy]-benzamide    4-{5-[(3,3-Dimethyl -butylamino)-methyl]-pyridin-2-yloxy}-benzamide    4-{5-[(3-Methyl-butylamino)-methyl]-pyridin-2-yloxy}-benzamide-   4-{3-Chloro-5-[(2-thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamide-   4-(3-Chloro-5-{[2-(3-chloro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide-   and pharmaceutically acceptable salts, solvates, enantiomers, and    mixtures of diastereomers thereof.

Also particularly preferred is a compound selected from the groupconsisting of:

-   6-[2-Chloro-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide,-   6-(2-Methoxy-4-pentylaminomethylphenoxy)nicotinamide,-   6-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide,-   6-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-methyl-phenoxy}-nicotinamide,-   6-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide,-   5-(2-Fluoro-4-pentylaminomethylphenoxy)pyridine-2-carboxamide,-   6-(4-{[2-(2-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide,-   4-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-benzamide,-   6-(4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-nicotinamide,-   a combination of one or more of the above, and a pharmaceutically    acceptable salt, solvate, enantiomer, diastereomer and    diastereomeric mixture thereof.

Most preferred is a compound selected from the group consisting of:

-   5-{2-Fluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-pyrazine-2-carboxamide

-   5-(2-Methoxy-4-pentylaminomethyl-phenoxy)-pyrazine-2-carboxamide

-   6-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide;    methanesulfonic acid salt

-   6-(2,3-Difluoro-4-pentylaminomethyl-phenoxy)-nicotinamide

-   5-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-pyrazine-2-carboxamide

-   6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinamide

-   5-{4-[(4,4-Dimethyl-pentylamino)-methyl]-2-methoxy-phenoxy}-pyrazine-2-carboxamide

-   5-(2-Methoxy-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

-   5-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-phenoxy}-pyrazine-2-carboxamide

-   5-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

-   6-{2-Methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide;    methanesulfonic acid salt

-   5-(2-Methyl-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

-   6-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-6-methoxy-phenoxy}-nicotinamide

-   5-(2-Fluoro-4-pentylaminomethyl-phenoxy)-pyrazine-2-carboxamide

-   3-Chloro-4-{4-[(3,3-dimethyl-butylamino)-methyl]-phenoxy}-benzamide

-   6-(4-{[2-(Tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide

-   6-{4-[2-(3,3-Dimethyl-butylamino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

-   6-{2-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

-   3,5-Difluoro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

-   6-{2,3,6-Trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

-   6-{2,6-Difluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

-   3-Fluoro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

-   and a pharmaceutically acceptable salt, solvate, enantiomer,    diastereomer and diastereomeric mixture thereof.

Preparing Compounds of the Invention

In a typical protocol, an optionally substituted benzonitrile orpyridine carboxamide or synthon thereof, having a leaving group such ashalogen, preferably fluoro, bromo, or chloro, or an alkylsulfonyl orother suitable leaving group is reacted with a nucleophilic group suchas for example, hydroxy phenylcarboxaldehyde or synthon or derivativethereof. For example according to Scheme 1,

optionally substituted 4-fluorobenzonitrile is reacted with optionallysubstituted 4-hydroxybenzaldehyde to afford the ether, compound 3, underbasic conditions. Basic conditions include the use of bases selectedfrom inorganic and organic bases. Examples of useful inorganic basesinclude but are not limited to potassium carbonate, sodium hydride,sodium carbonate, sodium hydroxide, potassium hydroxide, calciumcarbonate and cesium carbonate. Examples of organic bases include butare not limited to potassium hexamethyl disilazide, n-butyl lithium,Hexamethylphophoroustriamide, (HMPT), and the like. The basic conditionsare complemented by the presence of a solvent, preferably an organicsolvent. Preferred organic solvents include protic solvents or polaraprotic solvents. Most preferred solvents include dimethylformamide,methanol, dimethylacetamide (DMA), dimethylsulfoxide. A most preferredbasic reaction condition involves the use of potassium carbonate indimethylacetamide at temperatures of about 60 to 100° C.

The nitrile compound of formula 3 is converted to the carboxamide 4 byhydrolysis procedures known to one of skill in the art. For example, thecompound of formula 3 is reacted with potassium carbonate or othersuitable base in the presence of hydrogen peroxide in a suitable organicsolvent i.e. DMSO or DMF. The resulting amide compound 4 is reductivelyaminated with a suitably substituted amine. The reductive amination maybe performed in two steps or a single step depending on the stability ofthe intermediate imine. The compound 4 is reacted with a primary orsecondary amine (primary amine shown) in methanol as solvent. Molecularsieves may be added to enhance the efficiency of the imine formation ina second step the reducing agent, typically, sodium borohydride or otherhydride reducing agent is added to the reaction mixture. The progress ofthe reaction may be monitored by TLC, HPLC, LC-MS or other analyticaltechnique known to one of skill in the art to determine the substantialcompletion of each step and timing for the addition of the next reagent.The reductive amination of compound 4 results in the compound of formula5, which is a compound of the invention. Analogues of compounds 3 and 5having one or more substituent R groups may be prepared by usingappropriately substituted starting materials or by inter-conversion ofsubstituent functionality. For example an initial substituent R groupmay be protected and deprotected appropriately to achieve the desiredend substituent R. Alternatively an initial substituent, R may beconverted by known 1,2 or 3 step reactions to other desired Rsubstituents.

An alternate protocol illustrated in Scheme 2 shows the use of thecarboxamide starting material to prepare, for example, compounds havingthe pyridinyl B-ring.

The use of the carboxamide starting material is particularly preferredfor compounds of the invention where the B-ring is pyridinyl,pyridazinyl, pyrazinyl or pyrimidinyl group. The carboxamide may beintroduced as part of the starting material where the appropriatesurrogate for the B-ring is commercially available or may be preparedfor certain groups as discussed in the examples. For example, the use ofpyridine carboxamide, nicotinamide or substituted analogs thereof,results in substituted derivatives or analogs of compounds of formula 4aor 5a, which are also compounds of the present invention. Primary andsecondary amines are useful for the reductive amination to convertcompound (4a) to compound (5a). Examples of useful amines include butare not limited to phenethylamine, 3-methylbutylamine, propylamine,isopropylamine, benzylamine and isopentylamine.

Compounds prepared by this and other schemes disclosed herein or knownto one of skill in the art may further be converted to the acid additionsalt as shown for example, in Schem 2A.

Scheme 2A shows preparation of the hydrochloride salt (6a′) of compound5a of Schem 2 wherein RNH₂ is 3-methylbutylamine or other amine groupand R⁴ and R⁵ are both hydrogen. The compound 5a′ is dissolved inethanol and a slight excess (e.g 1.0 to 1.5 molar equivalents) of 1Nhydrochloric acid is added at temperatures ranging from about 0° C. toroom temperature. The mixture may be allowed to crystasllize over timewith or without cooling, or may be evaporated to afford thehydrochloride salt, which may be further purified by trituration with asuitable organic solvent such as toluene, hexanes, diethylether ormixtures thereof. Alternatively, anhydrous HCl may be bubbled into acold solution of compound 5a′ until the reaction is complete or thesolution is saturated, and the mixture worked up as appropriate. One ofskill in the art is aware of the nuances and the varied techniques forpreparating, isolating and purifying acid addition salts, and shouldachieve comparable results using methods appropariate for the particularsubstrate without undue experimentation.

A modified protocol for preparing compounds of the invention is providedin Scheme 3 wherein the nucleophilic displacement reaction to form theether linkage is performed towards the end of the synthesis rather thanearly on.

Under this protocol an appropriately substituted aminophenol isreductively aminated with benzaldehyde, which is optionally substitutedas appropriate. The reductive amination is accomplished in the presenceof sodium borohydride or other reducing agent and a suitable base.Alternatively, and preferably, di-tert-butyldicarbonate (Boc₂O) is usedto afford protection of the incipient free amine as the Boc-protectedamine. The resulting phenoxy compound 7 is then reacted with a B ringsource such as, for example, phenyl or pyridine carboxamide,benzonitrile or pyridino-nitrile or synthon thereof. The coupling of theB and A-ring sources is performed under basic conditions to afford theether 8a and 8b for the above example. The coupled product where itexists as a mixture of isomers as in 8a and 8b, the isomers may beseparated or used directly in the next step. In the next step, thenitrile group if present as in the current example is hydrolyzed to thecarboxamide as discussed previously. The protecting group may be removedby use of hydrochloric acid or trifluoroacetic acid using proceduresknown to one of skill in the art. One of skill in the art is aware thatappropriately substituted analogs of the compound of formula 10a or 10bmay be prepared by starting with appropriately substituted startingmaterials or surrogates thereof which may be converted to the desiredsubstituents.

Compounds of formula I having varying alkyl chain lengths on the aminoside chain may be prepared in one instance by carbonyl elongationreactions. An example is a modified Wittig type reaction as shown inScheme 4.

The protocol of Scheme 4 and known variations thereof allow manipulationof the amino side chain for chain length and/or substituents. Under thisprotocol, optionally substituted 4-hydroxy benzaldehyde i.e. compound 11is reacted with optionally substituted benzonitrile having a suitableleaving group, e.g. halo, alkylsulfonyl, etc. The nicotinonitrile 12 oranalog thereof, is then subjected to a carbonyl elongation reaction suchas, for example, the Wittig reaction and variations thereof. (seeOrganophosporus Agents in Organic Synthesis, J. I. G. Cadogan, Ed.,Academic Press London (1979); see also, J. March, Advanced OrganicChemistry, 3^(rd) Edition, Wiley Interscience, New York N.Y., (1995). Inthe example given, the aldehyde 12 is reacted with methoxymethyltriphenylphosphine (available from Aldrich chemical Company, Milwaukee,USA) using a strong base such as, for example, n-butyl lithium,sec-butyl lithium and the like, to generate the incipient carbanion. Theresulting vinymethyl ether 13 is hydrolyzed using a strong acid such as,p-toluenesulfonic acid, HCl or sulfuric acid to generate the newaldehyde. The aldehyde is then reacted with a suitable amine followed byreduction to afford the reductive amination product 14. Details of eachstep in the schemes disclosed herein are provided in the experimentalsection, or may be found in reference organic synthesis texts or areknown to one of skill in the art. Some reactions such as the formationof the ylide specie for the Wittig and related reactions perform betterat reduced temperatures ranging from about −10° C. to about −70° C.Other reactions perform better at elevated temperatures ranging fromabout 30° C. to about 150° C., and yet other reactions perform better atambient temperature ranging from about 15° C. to about 30° C.

Compounds of the invention wherein the groups R¹ and R² combine witheach other and with the nitrogen atom to form a nitrogen containingheterocycle may be prepared, for example, according to scheme 5.

According to Scheme 5, the reductive amination of aldehyde with amine isperformed using a cyclic amine having the desired ring size and/orsubstituents. For example, the reaction of compound optionallysubstituted cyclic amine such as for example, optionally substitutedpyrrolidine (as shown) with the aldehyde 4 results in the formation ofcompound 16 having the R¹ and R² combine together to form the nitrogencontaining heterocyclic amine.

Compounds of formula I wherein R¹ or R² combines with the A ring to forma nitrogen containing heterocycle may be prepared as shown in thefollowing scheme 6.

The scheme above, shows the preparation of the benzo[d]azepine ring as arepresentative example. As shown the reaction of 3-methoxyphenacetylchloride (17) with methylamino acetaldehyde dimethylacetal results inthe formation of compound 18. Compound (18) is cyclized to theazepin-2-one compound 19. Compound 19 is reduced to thetetrahydrobenzo[d]azepin-2-one compound using, for example, lithiumaluminum hydride in THF or 5% palladium on carbon in ethyl acetate. Thecompound is further deoxygenated and reduced to thetetrahydrobenzo[d]azepine compound 20. Compound 20 is first protected asthe trifluoroacetamide, de-methylated with boron tribromide in asuitable polar aprotic solvent, and then reacted with6-chloronicotinamide, for example, to form the corresponding etherproduct. The trifluoroacetamide protecting group is removed by basichydrolysis, i.e. ammonia in methanol, and substitution on the azepinenitrogen results in compounds of the invention 22. Such substitutionsmay be effected by using a base such as sodium or potassium carbonate inthe presence of the electrophile i.e. alkyl, benzyl or aryl halide.Detailed procedures for the practice of the above protocol, as withother protocols described above may be found in the experimentalsection. Also details for individual steps of protocols disclosed hereinmay be found in the literature or are known to one of skill in the art.

Compounds of formula I wherein the B-ring is a positional isomer ofpyridine may be prepared as shown for example in Scheme 7.

As shown above, diazotization followed by bromination of2-amino-5-fluoropyridine (23) affords the 2-bromo-5-fluoropyridinecompound 24. The 2-bromo-5-fluoropyridine compound is converted to theethoxycarbonyl derivative via a hydroxycarbonylation reaction followedby esterification of the incipient carboxylic group. The palladiumcatalyzed hydroxycarbonylation reaction is known to one of skill in theart and is also disclosed in general organic chemistry reference text.For a variant of the hyroxycarbonylation reaction using the triflateleaving group see Sandro Saccbi and Alessandro Lupi, Palladium CatalyzedHydroxycarbonylation of Vinyl and Aryl Triflates: Synthesis ofα,β-Unsaturated and Aromatic Carboxylic Acids, Tetrahedron Letters, Vol.33, No. 27, pp. 3939-3942, (1992). The resulting ester may be hydrolyzedto the acid, which is then converted to the carboxamide via a couplingreaction facilitated by a coupling agent such as EDCI for example.Alternatively the 2-bromo-5-fluoropyridine compound may be converted tothe nitrile by reaction with copper cyanide in a polar aprotic solventsuch as DMF. The nitrile is then hydrolyzed as discussed previously toafford the corresponding carboxamide 26. One of skill in the art isaware that palladium catalyzed cyanation reactions using copper cyanide,palladium source and ligand are available to effect the cyanationreaction discussed above with similar or possibly improved yields. Thecarboxamide compound 26 is reacted with a substituted or unsubstituted4-hydroxybenzaldehyde protected as the acetal 28. The resultingetherification product is then reductively aminated with an amine in thepresence of sodium borohydride or other suitable reducing agent toafford the compound of the invention 29 as shown.

Compounds of formula I wherein the B ring is pyrazinyl may be prepared,for example, according to scheme (8) below:

Compounds wherein R¹ and/or R² is independently a cyclic group, i.e.saturated or unsaturated monocyclic carbocycle may be prepared as shownbelow in Scheme 9. Scheme 9 is affected by reacting the amine 33incorporating the A-ring, with a halogeno-nicotinamide e.g.,6-chloronicotinamide or a halogeno-nicotinonitrile to form the compoundof the invention 34.

Where a halogeno-nicotinonitrile is used, the hydrolysis of theresulting nitrile to form the amide derivative has been disclosedpreviously. The amine 33 is itself prepared by reductive amination of4-hydroxy phenacetaldehyde and the respective amine. Thephenacetaldehyde may itself be purchased or prepared from thecorresponding benzaldehyde by carbonyl elongation reactions i.e. by theWittig or modified Wittig reaction as discussed previously.

An alternative protocol is shown in Scheme 10.

As shown in Scheme 10, an amine substrate having the A-ring, i.e.,4-hydroxyphenethyl amine is protected at the amine using, for example,the Boc-protecting group or other typical amino protecting groups. TheBoc-protected amine 35 is coupled to the B-ring component, i.e.,6-chloronicotinamide (shown) or nicotinonitrile or benzonitrile oranalog or derivative thereof. The coupled product is then de-protectedand reductively aminated with a cyclic ketone having the desired R¹and/or R² group per the structure and scope of formula I. For theexample shown, tertiary butyl dimethyl silyl (TBDMS) protected3-hydroxycyclohexanone 37 is reacted with the amine 36 having the A andB rings already in place, to form the desired compound of the invention38 upon desilylation.

The preferred reaction conditions for each step of the reactions orschemes disclosed herein are provided in the experimental section, orknown to one of skill in the art, or suggested in the literature orascertainable with minimal routine experimentation by one of skill inthe art following some or all the teachings disclosed and/or referencedherein. Substituents such as “R” and “R′” groups used in the schemes arefor illustration purposes only and are not intended to limit the scopeof the number and/or type of substituents. One of skill in the art isaware of substituent-types and multiplicities thereof that are suitableand/or possible for a particular position. In general, while aparticular substrate or compound is used for illustration purposes, nolimitation is implied the workability of the particular scheme for othercompounds within the ambit of the invention unless so stated. One ofskill in the art is aware that compounds of formula II may also beprepared by the schemes above and by procedures disclosed in theexperimental section.

Certain compounds of the invention may also be accessed by protocolssuch as Scheme 11. For example, compounds of formula I or II having “y”groups other than hydrogen may be more readily accessed by a Michaeladdition of nitromethane on an aldehyde e.g., aldehyde 39, having thedesired A ring substituents. The resulting product is reduced to affordthe saturated amine. When r is methyl the product 41 is deprotected byreaction with BBr₃, following procedures disclosed herein and/or knownto one of skill in the art. The resulting hydoprxyamine is optionallyprotected for example by use of a Boc-group to afford the compound 42.The protected amino compound 42 is then reacted with appropriatelysubstituted benzamide or nicotinonitrile or nicotinamide to afford acompound of formula I or II after further processing as describedpreviously.

Method of Using the Invention

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at mu, kappa, and/or delta opioidreceptors. As such, the present invention also provides a method forblocking a mu, kappa, delta receptor or receptor combination(heterodimer) thereof in a mammal comprising administering to saidmammal a receptor blocking dose of a compound of formula I or II.

The term “receptor blocking dose”, as used herein, means an amount of acompound of formula I or II necessary to block a mu, kappa, or deltareceptor or receptor combination (heterodimer) thereof followingadministration to a mammal requiring blocking of a mu, kappa, or deltareceptor or receptor combination (heterodimer) thereof.

The compounds of formula I or II or combinations thereof, are effectiveover a wide dosage range. For example, dosages per day will normallyfall within the range of about 0.05 to about 250 mg/kg of body weight.In the treatment of adult humans, the range of about 0.5 to about 100mg/kg, in single or divided doses, is preferred. However, it will beunderstood that the amount of the compound actually administered will bedetermined by a physician in light of the relevant circumstances,including the condition to be treated, the choice of compound to beadministered, the age, weight, and response of the individual patient,the severity of the patient's symptoms, and the chosen route ofadministration. Therefore, the above dosage ranges are not intended tolimit the scope of the invention in any way. The compounds may beadministered by a variety of routes such as the oral, transdermal,subcutaneous, intranasal, intramuscular and intravenous routes.

A variety of physiologic functions have been shown to be subject to orinfluenced by mu, kappa, or delta receptors or receptor combination(heterodimers) in the brain. As such, the compounds of the presentinvention are believed to have the ability to treat disorders associatedwith these receptors or combinations thereof, such as eating disorders,opioid overdose, depression, smoking, alcoholism, sexual dysfunction,shock, stroke, spinal damage and head trauma. As such, the presentinvention also provides methods of treating the above disorders byblocking the effect of agonists at a mu, kappa, delta receptors orreceptor combinations (heterodimer) thereof. The compounds of thepresent invention have been found to display excellent activity in anopioid receptor binding assay which measures the ability of thecompounds to block the mu, kappa, delta or receptor combination(heterodimer) thereof.

GTP-γ-S Binding Assay

An SPA-based GTP-γ-S assay format was developed based on previous opioid(Emmerson et al., J. Pharm Exp Ther 278,1121,1996; Horng et al., Societyfor Neuroscience Abstracts, 434.6, 2000) and muscarinic (DeLapp et al.,JPET 289, 946, 1999) assay formats. Membranes were re-suspended in 20 mMHEPES, 100 mM NaCl, 5 mM MgCl₂, 1 mM DTT, and 1 mM EDTA. Fifty (50) mLof GTP-γ-[35S], compound, membrane suspension (20 microgram/well), andwheat germ agglutinin coated SPA beads (1 mg/well) were added to clearbottom 96 well assay plates. GDP (200 mM) was added to the membranesolution prior to addition to the assay plates. Plates were sealed andincubated for four hours at room temperature then placed in arefrigerator overnight to allow the beads to settle. Signal stability at4° C. was determined to be >60 hours. Plates were warmed to roomtemperature and counted in a Wallac Microbeta scintillation counter. Forantagonist assays, specific agonists were added at the followingconcentrations: (MOR) DAMGO 1 micromolar, (DOR) DPDPE 30 nM, (KOR)U69593 300 nM. Kb's were determined by Cheng-Prusoff equation (see Chengand Prusoff, Biochem. Pharmacol. 22, 3099, 1973). Results obtained for arepresentative sample of compounds of the invention in the GTP-γ-SBinding Assay are shown in table 1 below.

TABLE 1 In Vitro Antagonism GTP- γ-S Kb (nM) Compound # Mu (nM) KappaDelta (nM) 475 0.843 7.859 17.489 476 0.281 3.378 8.900 478 0.410 4.4985.779 271 0.200 0.400 4.400 479 0.503 6.855 30.101 252 0.177 2.16614.121 253 0.068 0.355 0.708 256 0.072 0.894 0.677Ex-Vivo Receptor Binding

In order to bridge in vitro binding affinity and antagonist potency toin vivo potency and efficacy applicants have developed an ex vivoreceptor binding assay in rat brain. This assay measures the differencein association (binding) of a high affinity nonselective opioid receptorradioligand (3H-diprenorphine) in brain tissue isolated from animalsreceiving vehicle versus compound treatment (less binding of3H-diprenorphine=greater compound association with opioid receptors).Studies using the ex-vivo receptor binding assay have demonstrated apositive correlation between activity (potency and duration of activity)which also correlates to 24 hour efficacy in dietary induced obese rats.

Methods. An opioid receptor ex vivo binding assay measures3H-diprenorphine binding (0.1-0.4 nM affinity radioligand for mu, deltaand kappa receptors) in rat striatum/nucleus accumbens; a region of thebrain that contains a high density of mu, delta and kappa receptors,following oral administration of compounds. Experimentally, a screeningdose of 7 mg/kg, p.o. of compound or vehicle is administered to rats.Six hours following compound administration, the animals are sacrificedand the striatum/nucleus accumbens is isolated and homogenized in 10volumes (weight/volume) binding buffer. The homogenate is then used in ahomogenate binding assay using a saturating concentration of3H-diprenorphine for 30 minutes. The homogenization and assay isperformed at 4° C., to minimize compound redistribution in the in vitrobinding portion of the assay. Results are reported (Table 2) as %inhibition of diprenorphine binding, based on the difference in specificbinding between compound treated animals versus control animals treatedwith vehicle alone.

TABLE 2 Ex Vivo Binding [3H]-Diprenorphine % Inhibition of at 6 hoursCompound of 7 mg/kg of test Example No. compound 228 >65% 309 >60%271 >40% 253 >40% 481 83% 229 77% 420 75% 447 62% 263 62% 238 59% 44655% 227 55% 405 55% 431 54% 294 50% 256 40% 272 79% 246 58% 240 38%LY255582 >40% Naltrexone ® <40%

Acute Feeding Assay (Rat Obesity Assay)

The efficacy of compounds of the present invention has been furtherverified by the results of a Rat Obesity assay shown in Table 3. Theassay results show that compounds of the present invention achieveinhibition of opioid receptors at a level comparable to or superior tothat achieved with a previous clinical candidate compound LY255582disclosed and claimed in U.S. Pat. No. 4,891,379.

TABLE 3 Doses in ug/kg to Compound of achieve effective Example No.inhibition 290 3 227 0.3 228 0.3 271 0.3 263 ≦3 309 ≦3 253 ≦3 LY255582 1Naltrexone ® >10Indirect Calorimetry Assay

Twenty-four-hour energy expenditure (EE) and respiratory quotient (RQ)were measured by indirect calorimetry using an open circuit calorimetrysystem (Oxymax, Columbus Instruments Int. Corp., USA). RQ is the ratioof the volume of CO₂ produced (VCO₂) to the volume of O₂ consumed (VO₂).EE was calculated as the product of calorific value of oxygen (CV) andVO₂ per kilogram of body weight, where CV=3.815+1.232 (RQ). Totalcalories expended were calculated to determine daily fuel utilization.To calculate the proportion of protein, fat and carbohydrate that isused during that 24-hour period, we used Flatt's proposal (see, Flatt JP 1991 Assessment of daily and cumulative carbohydrate and fat balancesin mice. J Nutr Biochem 2:193-202.) and formulae as well as otherderived constants (see Elia M, Livesey G 1992 Energy expenditure andfuel selection in biological systems: the theory and practice ofcalculations based on indirect calorimetry and tracer methods. World RevNutr Diet 70:68-131.). Food consumption over the 24-hour period was alsomeasured. The minimum effective dose (MED) for inhibition of foodconsumption is reported as the lowest dose that caused a reduction infood consumption that was significantly different from vehicle treatedcontrols. Results obtained for a sample of compounds of the inventionwith the indirect calorimetry assay are shown below in Table 4.

TABLE 4 Inhibition of Feeding Energy Balance* Diet Induced Obese RatDiet Induced Minimum Effective Dose Obese Rat test Compound of (MED)dose 3 mg/kg, p.o. Example mg/kg, p.o. kcal/kg/day 290 3 −65 227 0.3 −68228 0.3 −81 271 0.3 −35 263 ≦3 −56 309 ≦3 −39 253 ≦3 −19 LY255582 1 −36Naltrexone ® >10 Not significant *Energy balance = caloric intake minusutilization (kcal/kg/day)

The indirect calorimetry assay above shows that the minimum effectivedose to inhibit food consumption at a level significantly different fromthe level achieved with a vehicle control dose was comparable or betterfor compounds of the present invention compared to a reference compound.

Formulation

A compound of the invention is preferably presented in the form of apharmaceutical formulation comprising a pharmaceutically acceptablecarrier, diluent or excipient and a compound of the invention. Suchcompositions will contain from about 0.1 percent by weight to about 90.0percent by weight of the compound of the invention (Active Ingredient).As such, the present invention also provides pharmaceutical formulationscomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient thereof.

In making the compositions of the present invention, the activeIngredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material that acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium), and soft and hard gelatincapsules.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

For oral administration, the Active Ingredient, a compound of thisinvention, may be admixed with carriers and diluents and molded intotablets or enclosed in gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the Active Ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as Active Ingredient any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Amount per Concentration Compound capsule (mg) by weight (%) ActiveIngredient 250 55 Starch dried 200 43 Magnesium stearate 10 2

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

Amount per Concentration Compound capsule (mg) by weight (%) ActiveIngredient 20 10 Starch 89 44.5 Microcrystalline 89 44.5 celluloseMagnesium stearate 2 1

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of active ingredient are made asfollows:

Amount per Concentration Compound capsule (mg) by weight (%) ActiveIngredient 100 30 Polyoxyethylene  50 mcg 0.02 Sorbitan monooleateStarch powder 250 69.98

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets each containing 10 mg of active ingredient are prepared asfollows:

Amount per Concentration Compound capsule (mg) by weight (%) ActiveIngredient 10 10 Starch 45 45 Microcrystalline 35 35 cellulosePolyvinylpyrrolidone 4 4 (as 10% solution in water) Sodium carboxymethyl4.5 4.5 starch Magnesium stearate 0.5 0.5 talc 1 1

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granules,which after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formula may be prepared using the ingredients below:

Compound Amount per capsule (mg) Percent by weight (%) Active Ingredient250 38 Cellulose 400 60 microcrystalline Silicon dioxide fumed 10 1.5Stearic acid 5 0.5

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are made asfollows:

Amount per 5 mL Compound suspension (ml) Active Ingredient 5 Sodiumcarboxymethyl 50 cellulose Syrup 1.25 Benzoic acid solution 0.10 Flavorq.v. Color q.v. Water q.s. to 5 mL

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

Concentration by weight Compound (percent) Active Ingredient 0.25Ethanol 29.75 Propellant 22 70.0 (chlorodifluoromethane)

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

EXAMPLE 1 6-[4-(2-Benzylamino-ethyl)-phenoxy]-nicotinamide

Step 1 4-(2-Benzylamino-ethyl)-phenol

Add benzaldehyde (7.5 mL, 74 mmol) to a stirred solution of tyramine(10.00 g, 73 mmol) and anhydrous methanol (90 mL). Bleat reaction toreflux for 1 h under nitrogen. Cool reaction to 0° C. and slowly addsodium borohydride (2.84 g, 75 mmol). Stir for 1 h at room temperatureand then concentrate on a rotary evaporator. Add water (100 mL) and stirfor 1.5 h at room temperature. Filter and wash with water to yield 10.11g (61%) of 4-(2-benzylamino-ethyl)-phenol: mass spectrum (ion spray):m/z=228.1 (M+1); ¹H NMR (DMSO-d₆): 9.14 (br s, 1H), 7.29-7.18 (m, 5H),6.96 (d, 2H), 6.65 (d, 2H), 3.69 (s, 2H), 2.67-2.60 (m, 4H), 2.02 (br s,1H).

Step 2

Add 6-chloronicotinamide (7.03 g, 44.90 mmol) to a stirred solution of4-(2-benzylamino-ethyl)-phenol (10.10 g, 44.43 mmol), potassiumcarbonate (15.35 g, 111.1 mmol), dimethylacetamide (138 mL), andisooctane (16 mL). Using a Dean-Stark trap, heat the reaction to refluxunder nitrogen for 6 h. Cool the reaction mixtures to room temperature,filter off the solids, and concentrate most of the solvent off on arotary evaporator. Take the residue up in ethyl acetate (200 mL) and add1N hydrochloric acid (200 mL). Stir for 15 minutes and filter off theprecipitate washing with ethyl acetate. Dissolve the solid in 400 mL ofboiling 1:1 methanol/water. To this solution add 5N sodium hydroxide (35mL) and allow the solution to cool to room temperature. Filter and washwith water to yield 19.74 g (83%) of6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide: mass spectrum (ionspray): m/z=348.1 (M+1); ¹H NMR (CDCl₃): 8.58 (d, 1H), 8.15 (dd, 1H),7.34-7.24 (m, 7H), 7.06 (d, 2H), 6.93 (d, 1H), 6.08 (br s, 2H), 3.82 (s,2H), 2.92 (t, 2H), 2.84 (t, 2H), 1.33 (br s, 1H).

EXAMPLE 2 6-{4-[2-(Benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide

Add sodium bicarbonate (0.0823 g, 0.980 mmol) to a stirred solution of6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3061 g, 0.881 mmol),(2-bromoethyl)benzene (0.135 mL, 0.988 mmol), and DMF (5 mL). Heat thereaction to reflux for 3 h under nitrogen and then cool to roomtemperature. Pour the reaction into water (50 mL) and extract withdiethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesiumsulfate and then filter off the magnesium sulfate. Concentrate on arotary evaporator and purify the crude product by flash chromatographyon silica gel eluting with 90% ethyl acetate/hexanes to yield 0.1538 g(39%) of 6-{4-[2-(benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide:mass spectrum (ion spray): m/z=452.1 (M+1); ¹H NMR (CDCl₃): 8.55 (d,1H), 8.13 (dd, 1H), 7.29-7.11 (m, 14H), 7.01 (d, 2H), 6.92 (d, 1H), 3.71(s, 1H), 2.94-2.77 (m, 9H).

By the method of example 1 the following compounds were prepared:

Mass spectrum (ion spray): m/z Example Name (M + 1) ¹H NMR(CDCl₃) 36-(4-{2-[Benzyl-(3- 466.1 8.53(d, 1H), 8.11(dd, 1H), 7.29-7.11(m,phenyl-propyl)-amino]- 14H), 7.03-7.00(m, 2H), 6.91(d, 1H),ethyl}-phenoxy)- 3.63(s, 2H), 2.77-2.68(m, 4H), nicotinamide2.59-2.52(m, 4H), 1.83-1.75(m, 2H) 4 6-{4-[2-(Benzyl-hexyl- 433.18.56(d, 1H), 8.13(dd, 1H), 7.29-7.15(m, amino)-ethyl]-phenoxy}- 9H),7.01(d, 2H), 6.92(dd, 1H), 3.62(s, nicotinamide 2H), 2.78-2.66(m, 4H),2.48(t, 2H), 1.48-1.43(m, 2H), 1.30-1.23(m, 6H), 0.86(t, 3H) 56-{4-[2-(Benzyl-heptyl- 446.2 8.56(d, 1H), 8.13(dd, 1H), 7.31-7.15(m,amino)-ethyl]-phenoxy}- 7H), 7.01(d, 2H), 6.91(d, 1H), 5.85(br s,nicotinamide 2H), 3.62(s, 2H), 2.78-2.66(m, 4H), 2.48(t, 2H),1.48-1.45(m, 2H), 1.29-1.24(m, 8H), 0.86(t, 3H) 6 6-(4-{2-[Benzyl-(5-446.1 8.55(dd, 1H), 8.13(dd, 1H), methyl-hexyl)-amino]- 7.29-7.16(m,9H), 7.03-6.98(m, 2H), 6.92(dd, ethyl}-phenoxy)- 1H), 3.62(s, 2H),2.78-2.67(m, 4H), nicotinamide 2.48(t, 2H), 1.52-1.41(m, 3H),1.29-1.21(m, 2H), 1.15-1.10(m, 2H), 0.84(d, 6H) 7 6-[4-(2-{Benzyl-[2-(3-486.2 8.55(dd, 1H), 8.14(dd, 1H), chloro-phenyl)-ethyl]- 7.28-6.91(m,16H), 3.69(s, 2H), 2.78-2.69(m, 8H) amino}-ethyl)-phenoxy]- nicotinamide8 6-(4-{2-[Benzyl-(3- 472.2 8.55(d, 1H), 8.13(dd, 1H), 7.29-7.15(m,cyclohexyl-propyl)- 9H), 7.01(d, 2H), 6.92(d, 1H), 3.62(s,amino]-ethyl}-phenoxy)- 2H), 2.78-2.67(m, 4H), 2.46(t, 2H), nicotinamide1.67-1.46(m, 7H), 1.19-1.12(m, 6H), 0.87-0.82(m, 2H) 96-(4-{2-[Benzyl-(3-o- 480.0 8.54(d, 1H), 8.13(dd, 1H), 7.31-7.00(m,tolyl-propyl)-amino]- 15H), 6.93(d, 1H), 3.67(s, 2H), ethyl}-phenoxy)-2.78-2.74(m, 4H), 2.62-2.55(m, 4H), 2.28(s, nicotinamide 3H),1.80-1.73(m, 2H) 10 6-(4-{2-[Benzyl-(3- 472.1 8.55(dd, 1H), 8.14(dd,1H), thiophen-2-yl-propyl)- 7.31-6.72(m, 15H), 3.65(s, 2H), 2.83-2.71(m,amino]-ethyl}-phenoxy)- 6H), 2.58(t, 2H), 1.89-1.60(m, 2H) nicotinamide

By the method of example 2 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB- Mass PhenylColumn spectrum 4.6 mm × Ex- (ion spray): 15 cm × 5 micron am- m/zRetention Time ple Name (M + 1) Purity (minutes) 116-{4-[2-(Benzyl-pentyl- 418.1 98.0 8.28 amino)-ethyl]-phenoxy}-nicotinamide 12 6-(4-{2-[Benzyl-(3- 458.4 96.6 8.94 cyclopentyl-propyl)-amino]-ethyl}-phenoxy)- nicotinamide 13 6-[4-(2-{Benzyl-[2-(2- 470.398.0 8.44 fluoro-phenyl)-ethyl]- amino}-ethyl)-phenoxy]- nicotinamide

EXAMPLE 14 6-[4-(2-Dibenzylamino-ethyl)-phenoxy]-nicotinamide

Compound of Example 14 is prepared by the method of Example 2.

EXAMPLES 15A-15E Step 1 1-(2-Bromo-ethyl)-3-chloro-benzene

Add triphenylphoshpine (3.90 g, 14.9 mmol) to a stirred solution of3-chlorophenethyl alcohol (2.0 mL, 14.8 mmol), carbon tetrabromide (4.91g, 14.8 mmol) and anhydrous dichloromethane (100 mL). Stir for 5 h undernitrogen at room temperature, and then wash with water (100 mL) andbrine (100 mL). Dry the dichloromethane layer over magnesium sulfate,filter, and concentrate on a rotary evaporator to give the crudeproduct. The crude product is purified by flash chromatography on silicagel eluting with 100% hexanes to yield 2.30 g (71%) of1-(2-bromo-ethyl)-3-chloro-benzene: TLC: R_(f) in 100% hexanes: 0.27; ¹HNMR (CDCl₃): 7.26-7.11 (m, 3H), 7.09-7.07 (m, 1H), 3.54 (t, 2H), 3.12(t, 2H).

Step 2

Add sodium triacetoxyborohydride (0.2600 g, 1.227 mmol) to a stirredsolution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3058 g,0.8802 mmol), benzaldehyde (0.092 mL, 0.905 mmol), glacial acetic acid(0.052 mL, 0.908 mmol) and 1,2-dichloroethane (8 mL). Stir for 18 h atroom temperature under nitrogen. Pour the reaction into 1N sodiumhydroxide (50 mL) and extract with diethyl ether (3×50 mL). Wash thediethyl ether extracts with brine, dry over magnesium sulfate, filter,and concentrate on a rotary evaporator to give the crude product. Thecrude product is purified by flash chromatography on silica gel elutingwith 75% ethyl acetate/hexanes to yield 0.2501 g (65%) of6-[4-(2-dibenzylamino-ethyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 8.14 minutes, Purity: 99.7%; mass spectrum (ion spray):m/z=438.0 (M+1).

The following compounds (Examples 15A-15E) were prepared from thecorresponding commercially available alcohols except examples1-(3-bromo-propyl)-2-methyl-benzene and 2-(3-bromo-propyl)-thiophene inwhich the starting alcohols were synthesized:

Example TLC: R_(f) in No. Name 100% Hexanes ¹H NMR (CDCl₃) 15A(3-Bromo-propyl)- 0.55 3.38(t, 2H), 1.89-1.38(m, 11H, 1.11-1.02(m, 2H)cyclopentane 15B (3-Bromo-propyl)- 0.55 3.37(t, 2H), 1.87-1.81(m, 2H),1.69-1.59(m, 5H), cyclohexane 1.31-1.06(m, 6H), 0.91-0.83(m, 2H) 15C1-(2-Bromo-ethyl)- 0.28 7.30-7.24(m, 1H), 6.98-6.89(m, 3H), 3.55(t, 2H),3-fluoro-benzne 3.15(t, 2H) 15D 1-(3-Bromo- 0.22 7.17-7.12(m, 4H),3.45(t, 2H), 2.78(t, 2H), 2.33(s, propyl)-2-methyl- 3H), 2.17-2.10(m,2H) benzene 15E 2-(3-Bromo- 0.2 7.16-7.13(m, 1H), 6.95-6.92(m, 1H),6.85-6.83(m, propyl)-thiophene 1H), 3.44(t, 2H), 3.02(t, 2H),2.25-2.18(m, 2H)

Preparing Alcohol Starting Material for Example 15D3-o-Tolyl-propan-1-ol

Add 2-methylhydrocinnamic acid (18.4 mmol) to anhydrous tetrahydrofuran(100 mL) and cool to 0° C. Slowly add lithium aluminum hydride (2.20 g,58.0 mmol) and remove the ice bath after 20 minutes. Stir at roomtemperature under nitrogen for 18 h. Cool the reaction to 0° C. andquench the reaction by slowly adding water (2.2 mL), 15% sodiumhydroxide (2.2 mL), and water (6.6 mL). Filter off the aluminum salts.Add brine (100 mL) and 5 N sodium hydroxide (30 mL) to the filtrate andextract with ethyl acetate (3×100 mL). Dry the ethyl acetate extractswith magnesium sulfate, filter, and concentrate on a rotary evaporatorto yield 2.65 g (96%) of 3-o-tolyl-propan-1-ol: ¹H NMR (CDCl₃):7.18-7.10 (m, 4H), 3.72 (t, 2H), 2.72-2.69 (m, 2H), 2.33 (s, 3H),1.90-1.83 (m, 2H), 1.60 (br s, 1H).

Preparing Alcohol Starting Material for Example 15E3-Thiophen-2-yl-propan-1-ol

Using a method similar to example 15D, using 3-(2-thienyl)propanoic acidaffords the title compound: ¹H NMR (CDCl₃): 7.12 (dd, 1H), 6.92 (dd,1H), 6.82-6.80 (m, 1H), 3.70 (t, 2H), 2.96-2.92 (m, 2H), 1.98-1.91 (m,2H), 1.67 (br s, 1H).

EXAMPLE 166-(4-{2-[Benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Step 1 3-Trimethylammonium-1-phenyl-propan-1-one iodide

Add concentrated hydrochloric acid (0.090 mL, 1.1 mmol) to a stirredsolution of acetophenone (5.0 mL, 43 mmol), paraformaldehyde (2.15 g),dimethylamine hydrochloride (4.54 g, 56 mmol), and ethanol (15 mL). Heatthe reaction to reflux for 18 h under nitrogen. Cool the reaction toroom temperature, pour it into 1 N sodium hydroxide (150 mL), andextract with diethyl ether (3×150 mL). Dry the diethyl ether extractsover magnesium sulfate, filter, and concentrate on a rotary evaporatorto give the crude product. Dissolve the crude product in ethanol (70 mL)and add iodomethane (3.2 mL, 51 mmol). Stir the reaction at roomtemperature for 18 h under nitrogen. Filter and wash with ethanolfollowed by diethyl ether to yield 12.56 g (92%) of3-trimethylammonium-1-phenyl-propan-1-one iodide: mass spectrum (ionspray): m/z=193.0 (M+1); ¹H NMR (DMSO-d₆): 8.08-8.06 (m, 2H), 7.72-7.67(m, 1H), 7.60-7.55 (m, 2H), 3.70 (s, 4H), 3.14 (s, 6H), 3.11 (s, 3H).

Step 2

Add 3-trimethylammonium-1-phenyl-propan-1-one iodide (0.3612 g, 1.132mmol) to a stirred solution of6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3041 g, 0.8753mmol), sodium carbonate (0.1862 g, 1.757 mmol), and dimethylformamide (5mL). Bubble nitrogen through the reaction for 18 h at room temperature.Pour the reaction into 1 N sodium hydroxide (50 mL) and extract withdiethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesiumsulfate, filter, and concentrate on a rotary evaporator to give thecrude product. The crude product is purified by flash chromatography onsilica gel eluting with 90% ethyl acetate/hexanes to yield 0.1910 g(46%) of6-(4-{2-[benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide:mass spectrum (ion spray): m/z=480.1 (M+1); ¹H NMR (CDCl₃): 8.57 (d,1H), 8.15 (dd, 1H), 7.90-7.88 (m, 2H), 7.57-7.53 (m, 1H), 7.46-7.42 (m,2H), 7.28-7.15 (m, 9H), 7.04-7.00 (m, 2H), 6.93 (d, 1H), 3.71 (s, 2H),3.13-3.01 (m, 4H), 2.78 (s, 4H).

EXAMPLE 176-(4-{2-[Benzyl-(3-oxo-3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Step 1 3-Trimethylammonium-1-thiophen-2-yl-propan-1-one iodide

Using a method similar to example 16, using 2-acetylthiophene affordsthe title compound: mass spectrum (ion spray): m/z=199.0 (M+1); ¹H NMR(DMSO-d₆): 8.12-8.04 (m, 2H), 7.32-7.28 (m, 1H), 3.70-3.61 (m, 4H), 3.11(s, 6H), 3.09 (s, 3H).

Step 2

Using a method similar to example 16, using3-trimethylammonium-1-thiophen-2-yl-propan-1-one iodide affords thetitle compound: mass spectrum (ion spray): m/z=486.3 (M+1); ¹H NMR(CDCl₃): 8.57 (d, 1H), 8.15 (dd, 1H), 7.63-7.60 (m, 2H), 7.29-7.01 (m,12H), 6.93 (d, 1H), 3.71 (s, 2H), 3.04 (s, 4H), 2.78 (br s, 4H).

EXAMPLE 186-(4-{2-[Benzyl-(3-cyclohexyl-3-oxo-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Step 1 1-Cyclohexyl-3-trimethylammonium-propan-1-one iodide

Using a method similar to example 16, using cyclohexyl methyl ketoneaffords the title compound: mass spectrum (ion spray): m/z=198.2 (M+1);¹H NMR (DMSO-d₆): 3.51-3.47 (m, 4H), 3.11 (s, 6H), 3.05 (s, 3H),2.49-2.42 (m, 1H), 1.87-1.84 (m, 2H), 1.73-1.60 (m, 3H), 1.31-1.12 (m,5H).

Step 2

Using a method similar to example 16, using1-cyclohexyl-3-trimethylammonium-propan-1-one iodide affords the titlecompound. Mass spectrum (ion spray): m/z=486.1 (M+1); ¹H NMR (CDCl₃):8.58 (d, 1H), 8.15 (dd, 1H), 7.31-7.15 (m, 9H), 7.04-7.01 (m, 2H), 6.93(d, 1H), 3.63 (s, 2H), 2.87-2.57 (m, 8H), 2.30-2.24 (m, 1H), 1.81-1.64(m, 5H), 1.33-1.15 (m, 5H).

EXAMPLE 196-(4-{2-[Benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Add methanol (10 mL) to6-(4-{2-[benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide(0.1871 g, 0.3901 mmol) and cool to 0° C. Add sodium borohydride (0.0664g, 1.756 mmol) and stir for 1.5 h at 0° C. under nitrogen. Pour thereaction into brine (50 mL) and extract with diethyl ether (3×50 mL).Dry the diethyl ether extracts over magnesium sulfate, filter, andconcentrate on a rotary evaporator to give the crude product. The crudeproduct is purified by flash chromatography on silica gel eluting with100% ethyl acetate to yield 0.0239 g (13%) of6-(4-{2-[benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide:HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6mm×15 cm×5 micron: Retention time: 8.07 minutes, Purity: 99.9%; massspectrum (ion spray): m/z=482.3 (M+1).

EXAMPLE 206-(4-{2-[Benzyl-(3-hydroxy-3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Using a method similar to example 19, using6-(4-{2-[benzyl-(3-oxo-3-thiophen-2-yl-propyl)-amino]-ethyl}-phenoxy)-nicotinamideaffords the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water)Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 7.93minutes, Purity: 99.2%; mass spectrum (ion spray): m/z=488.0 (M+1).

EXAMPLE 216-(4-{2-[Benzyl-(3-cyclohexyl-3-hydroxy-propyl)-amino]-ethyl}-phenoxy)-nicotinamide

Using a method similar to example 19, using6-(4-{2-[benzyl-(3-cyclohexyl-3-oxo-propyl)-amino]-ethyl}-phenoxy)-nicotinamideaffords the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water)Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.49minutes, Purity: 99.0%; mass spectrum (ion spray): m/z=488.1 (M+1).

EXAMPLE 22 6-{4-[2-(3-Phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide

Add 1-chloroethylchloroformate (0.056 mL, 0.52 mmol) to a stirredsolution of6-(4-{2-[benzyl-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide(0.1211 g, 0.2603 mmol) (Example 3) and 1,2-dichloroethane (5 mL). Beatthe reaction to reflux under nitrogen for 1.5 h. Add methanol (7 mL) andheat at reflux under nitrogen for 1 h. Cool the reaction to roomtemperature and add 2 M ammonia in methanol (5 mL). Concentrate on arotary evaporator to give the crude product. The crude product ispurified by flash chromatography on silica gel eluting with 1%concentrated ammonium hydroxide/10% ethanol/chloroform to yield 0.0654 g(67%) of 6-{4-[2-(3-phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide:HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6mm×15 cm×5 micron: Retention time: 7.48 minutes, Purity: 99.2%; massspectrum (ion spray): m/z=376.2 (M+1).

By the method of example 22 the following compounds were prepared fromthe corresponding compounds prepared in examples 2-14:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Mass spectrum ZorbaxSB-Phenyl Column (ion spray): 4.6 mm × 15 cm × 5 micron Example Name m/z(M + 1) Purity Retention Time (minutes) 23 6-[4-(2-Phenethylamino- 362.198.9 5.28 ethyl)-phenoxy]-nicotinamide 24 6-[4-(2-Hexylamino-ethyl)-342.1 99.2 7.01 phenoxy]-nicotinamide 25 6-[4-(2-Heptylamino-ethyl)-356.2 99.8 8.13 phenoxy]-nicotinamide 26 6-[4-(2-Pentylamino-ethyl)-328.1 98.7 4.44 phenoxy]-nicotinamide 27 6-{4-[2-(5-Methyl- 356.1 99.97.78 hexylamino)-ethyl]- phenoxy}-nicotinamide 286-(4-{2-[2-(3-Chloro-phenyl)- 396.0 99.3 7.71ethylamino]-ethyl}-phenoxy)- nicotinamide 29 6-{4-[2-(3-Cyclopentyl-368.2 98.4 7.99 propylamino)-ethyl]- phenoxy}-nicotinamide 306-{4-[2-(3-Cyclohexyl- 382.1 98.1 8.29 propylamino)-ethyl]-phenoxy}-nicotinamide 31 6-(4-{2-[2-(3-Fluoro-phenyl)- 380.1 99.1 1.43ethylamino]-ethyl}-phenoxy)- nicotinamide 32 6-{4-[2-(3-o-Tolyl- 390.199.1 7.88 propylamino)-ethyl]- phenoxy}-nicotinamide 336-{4-[2-(3-Thiophen-2-yl- 382.1 98.6 5.4 propylamino)-ethyl]-phenoxy}-nicotinamide

EXAMPLE 34 6-[4-(2-Amino-ethyl)-phenoxy]-nicotinamide

Step 1 [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester

Add di-tert-butyl dicarbonate (9.75 g, 44.7 mmol) to a stirred solutionof tyramine (5.00 g, 36.5 mmol) and anhydrous tetrahydrofuran. Stir thereaction at room temperature for 18 h under nitrogen. Concentrate thereaction to give the crude product. The crude product is purified byflash chromatography on silica gel eluting with 35% ethylacetate/hexanes to yield 7.56 g (87%) of[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester: massspectrum (ion spray): m/z=236.1 (M−1); ¹H NMR (CDCl₃): 7.01 (d, 2H),6.77 (d, 2H), 6.10 (br s, 1H), 4.61 (br s, 1H), 3.34-3.32 (m, 2H),2.72-2.68 (m, 2H), 1.44 (s, 9H).

Step 2 {2-[4-(5-Carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester

Add potassium tert-butoxide (4.28 g, 36.2 mmol) to a stirred solution of[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (6.40 g,27.0 mmol) and anhydrous tetrahydrofuran (120 mL). Stir for 30 minutesunder nitrogen at room temperature. Add 6-chloronicotinamide (4.27 g,27.2 mmol) and heat to reflux for 18 h under nitrogen. Cool to roomtemperature, pour the reaction mixture into, brine (150 mL), and extractwith diethyl ether (3×150 mL). Dry the diethyl ether extracts overmagnesium sulfate, filter, and concentrate on a rotary evaporator togive the crude product. The crude product is purified by flashchromatography on silica gel eluting with 0.7% concentrated ammoniumhydroxide/7% ethanol/chloroform to yield 4.46 g (46%) of{2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester: mass spectrum (ion spray): m/z=358.1 (M+1); ¹H NMR(DMSO-d₆): 8.58 (d, 1H), 8.22 (dd, 1H), 8.02 (br s, 1H), 7.46 (br s,1H), 7.23 (d, 2H), 7.06-7.02 (m, 3H), 6.92-6.89 (m, 1H), 3.17-3.12 (m,2H), 2.69 (t, 2H), 1.35 (s, 9H).

Step 3

Add dichloromethlane (60 mL) to the compound of Example 33 Step 2 (5.12g, 14.3 mmol). To this slurry add trifluoroacetic acid (32.0 mL, 415mmol) and stir under nitrogen for 1.5 h. Divide the reaction into threeequal aliquots and load each aliquot onto a 10 g prepacked SCXcartridge. Wash with methanol (200 mL) and elute the product off thecartridge with 2 M ammonia in methanol (100 mL). Combine the 2 M ammoniain methanol washes from the three cartridges and concentrate on a rotaryevaporator to give 3.11 g (84%) of6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray):m/z=258.1 (M+1); ¹H NMR (DMSO-d₆): 8.61 (d, 1H), 8.25 (dd, 1H), 8.04 (s,1H), 7.49 (s, 1H), 7.30-7.23 (m, 2H), 7.11-7.03 (m, 3H), 2.80-2.63 (m,4H), 1.89 (br s, 2H).

EXAMPLE 35 6-{4-[2-(2-Methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide

Add three-angstrom molecular sieves to a stirred solution of6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1000 g, 0.3887 mmol)(compound of example 33), 2-methoxybenzaldehyde (0.047 mL, 0.39 mmol),and methanol (5 mL). Agitate the reaction for 18 h on a platform shakerat room temperature. Add sodium borohydride and agitate for 1 h at roomtemperature. Filter to remove the molecular sieves and load the reactionmixture directly onto a 10 g prepacked SCX cartridge. Flush withmethanol (150 mL) and elute the product off the SCX cartridge with 2 Mammonia in methanol (50 mL). Concentrate on a rotary evaporator to give0.1253 g (85%) of6-{4-[2-(2-methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide: HPLC(30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6mm×15 cm×5 micron: Retention time: 4.14 minutes, Purity: 97.9%; massspectrum (ion spray): m/z=378.1 (M+1).

By the method of example 34 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn Mass 4.6 mm × 15 cm × spectrum 5 micron (ion spray): RetentionTime Example Name m/z (M + 1) Purity (minutes) 366-{4-[2-(3-Fluoro-benzylamino)- 366.1 99.0 3.69ethyl]-phenoxy}-nicotinamide 37 6-{4-[2-(3-Chloro-benzylamino)- 382.099.2 5.22 ethyl]-phenoxy}-nicotinamide 38 6-{4-[2-(3,4-Dichloro- 416.099.0 7.73 benzylamino)-ethyl]-phenoxy}- nicotinamide 396-{4-[2-(3-Trifluoromethyl- 416.1 99.1 7.52benzylamino)-ethyl]-phenoxy}- nicotinamide 406-{4-[2-(4-Cyano-benzylamino)- 373.1 90.8 3.00ethyl]-phenoxy}-nicotinamide 41 6-{4-[2-(4-Fluoro-benzylamino)- 366.1100.0 3.76 ethyl]-phenoxy}-nicotinamide 426-{4-[2-(4-Methyl-benzylamino)- 362.1 98.6 4.92ethyl]-phenoxy}-nicotinamide 43 6-{4-[2-(3,5-Bis-trifluoromethyl- 484.098.7 8.30 benzylamino)-ethyl]-phenoxy}- nicotinamide 446-{4-[2-(2,6-Difluoro- 384.1 100.0 3.13 benzylamino)-ethyl]-phenoxy}-nicotinamide 45 6-{4-[2-(3,5-Difluoro- 384.1 98.4 4.25benzylamino)-ethyl]-phenoxy}- nicotinamide 46 6-{4-[2-(4-Acetylamino-405.1 99.3 2.12 benzylamino)-ethyl]-phenoxy}- nicotinamide 476-{4-[2-(2-Trifluoromethyl- 416.1 99.1 5.87benzylamino)-ethyl]-phenoxy}- nicotinamide 486-{4-[2-(2-Methyl-benzylamino)- 362.1 98.7 4.13ethyl]-phenoxy}-nicotinamide 49 6-{4-[2-(3-Methoxy- 378.1 98.5 3.70benzylamino)-ethyl]-phenoxy}- nicotinamide 506-{4-[2-(4-Chloro-benzylamino)- 382.0 99.4 5.11ethyl]-phenoxy}-nicotinamide 51 6-{4-[2-(4-Phenoxy- 440.1 99.4 8.19benzylamino)-ethyl]-phenoxy}- nicotinamide 52 6-{4-[2-(4-Methoxy- 378.198.7 3.56 benzylamino)-ethyl]-phenoxy}- nicotinamide 536-{4-[2-(4-Trifluoromethyl- 416.1 99.4 7.46benzylamino)-ethyl]-phenoxy}- nicotinamide 546-{4-[2-(3-Oxo-2,3-dihydro-1H- 389.1 95.8 2.05isoindol-1-ylamino)-ethyl]- phenoxy}-nicotinamide 556-{4-[2-(4-Trifluoromethoxy- 432.1 99.5 7.79benzylamino)-ethyl]-phenoxy}- nicotinamide 566-{4-[2-(3-Trifluoromethoxy- 432.1 99.3 7.72benzylamino)-ethyl]-phenoxy}- nicotinamide 576-(4-{2-[(Thiophen-2-ylmethyl)- 354.0 99.1 2.63 amino]-ethyl}-phenoxy)-nicotinamide 58 6-(4-{2-[(Furan-2-ylmethyl)- 338.1 99.0 2.27amino]-ethyl}-phenoxy)- nicotinamide 59 6-[4-(2-Octylamino-ethyl)- 370.296.7 8.34 phenoxy]-nicotinamide 60 6-[4-(2-Cyclohexylamino-ethyl)- 340.290.4 3.04 phenoxy]-nicotinamide 61 6-{4-[2-(Cyclohexylmethyl- 354.2 98.75.10 amino)-ethyl]-phenoxy}- nicotinamide 62 6-[4-(2-Propylamino-ethyl)-300.1 96.8 2.07 phenoxy]-nicotinamide 63 6-[4-(2-Butylamino-ethyl)-314.1 97.3 2.57 phenoxy]-nicotinamide 64 6-[4-(2-Isopropylamino-ethyl)-300.1 83.0 1.99 phenoxy]-nicotinamide 65 6-[4-(2-Isobutylamino-ethyl)-314.1 97.0 2.40 phenoxy]-nicotinamide 66 6-{4-[2-(3-Methyl-butylamino)-328.2 98.1 3.44 ethyl]-phenoxy}-nicotinamide 676-(4-{2-[(Pyridin-4-ylmethyl)- 349.1 96.8 1.54 amino]-ethyl}-phenoxy)-nicotinamide 68 6-(4-{2-[(Pyridin-2-ylmethyl)- 349.1 84.4 2.07amino]-ethyl}-phenoxy)- nicotinamide 69 6-(4-{2-[(5-Methyl-furan-2-352.1 98.5 2.98 ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 706-(4-{2-[(3-Methyl-thiophen-2- 368.1 93.8 3.45 ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide 71 6-(4-{2-[(5-Methyl-thiophen-2- 368.1 97.9 3.80ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 726-(4-{2-[(Thiophen-3-ylmethyl)- 354.1 98.5 2.80 amino]-ethyl}-phenoxy)-nicotinamide 73 6-[4-(2-Ethylamino-ethyl)- 286.1 100.0 2.43phenoxy]-nicotinamide 74 6-{4-[2-(4-Hydroxy- 364.2 98.9 2.42benzylamino)-ethyl]-phenoxy}- nicotinamide 75 6-{4-[2-(3-Hydroxy- 364.299.4 2.43 benzylamino)-ethyl]-phenoxy}- nicotinamide 766-{4-[2-(3-Phenyl-prop-2- 372.2 96.9 6.41 ynylamino)-ethyl]-phenoxy}-nicotinamide 77 6-(4-{2-[(Furan-3-ylmethyl)- 338.2 99.7 2.47amino]-ethyl}-phenoxy)- nicotinamide 78 6-(4-{2-[(Benzofuran-2- 388.298.4 5.48 ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 796-(4-{2-[(5-Ethyl-furan-2- 366.2 99.2 4.62 ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide 80 6-(4-{2-[(5-Chloro-thiophen-2- 388.1 99.1 4.54ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 816-(4-{2-[(4,5-Dimethyl-furan-2- 366.2 99.8 4.51 ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide 82 6-(4-{2-[(4-Chloro-1-methyl-1H- 386.1 99.6 2.42pyrazol-3-ylmethyl)-amino]- ethyl}-phenoxy)-nicotinamide 836-(4-{2-[(Thiazol-2-ylmethyl)- 355.1 87.4 2.02 amino]-ethyl}-phenoxy)-nicotinamide 84 6-(4-{2-[(2-Methyl-1H-imidazol- 352.2 100.0 100.004-ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 856-{4-[2-(3,5-Di-tert-butyl-4- 476.2 88.0 8.77hydroxy-benzylamino)-ethyl]- phenoxy}-nicotinamide 866-{4-[2-(2-Fluoro-benzylamino)- 366.1 98.3 3.21ethyl]-phenoxy}-nicotinamide 87 6-{4-[2-(3-Phenoxy- 440.1 94.1 8.20benzylamino)-ethyl]-phenoxy}- nicotinamide 886-{4-[2-(2-Chloro-benzylamino)- 382.0 91.3 4.04ethyl]-phenoxy}-nicotinamide 89 6-{4-[2-(3-Cyano-benzylamino)- 373.196.4 3.25 ethyl]-phenoxy}-nicotinamide 906-{4-[2-(3-Methyl-benzylamino)- 362.1 92.8 4.80ethyl]-phenoxy}-nicotinamide 91 6-(4-{2-[(1H-Imidazol-4- 338.1 90.5 1.53ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 926-(4-{2-[(Pyridin-3-ylmethyl)- 349.1 95.5 1.56 amino]-ethyl}-phenoxy)-nicotinamide 93 6-{4-[2-(2-Phenoxy-ethylamino)- 378.1 85.7 4.67ethyl]-phenoxy}-nicotinamide 94 6-{4-[2-(3-Fluoro-4-hydroxy- 382.0 83.32.49 benzylamino)-ethyl]-phenoxy}- nicotinamide 956-(4-{2-[(2-Butyl-1H-imidazol-4- 394.1 94.2 1.60ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 966-(4-{2-[(Benzo[b]thiophen-3- 404.0 89.1 6.70 ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide 97 6-(4-{2-[(3-Phenyl-1H-pyrazol-4- 414.1 99.42.96 ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 986-[4-(2-Allylamino-ethyl)- 297.8 98.6 1.68 phenoxy]-nicotinamide 996-{4-[2-(4-Imidazol-1-yl- 414.1 98.4 1.58 benzylamino)-ethyl]-phenoxy}-nicotinamide 100 6-(4-{2-[(3-Methyl- 418.1 99.5 7.76benzo[b]thiophen-2-ylmethyl)- amino]-ethyl}-phenoxy)- nicotinamide 1016-{4-[2-(4-Methyl-pent-2- 340.1 59.2 4.74 enylamino)-ethyl]-phenoxy}-nicotinamide 102 6-{4-[2-(2-Trifluoromethoxy- 432.1 92.2 7.13benzylamino)-ethyl]-phenoxy}- nicotinamide 1036-(4-{2-[(2-Piperidin-1-yl-thiazol- 438.1 95.8 1.655-ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 1046-{4-[2-(4-Cyclohexyl- 396.2 76.1 8.61 butylamino)-ethyl]-phenoxy}-nicotinamide 105 6-{4-[2-(2-Cyclohexyl- 368.2 90.6 7.78ethylamino)-ethyl]-phenoxy}- nicotinamide 1066-{4-[2-(2-Chloro-6-fluoro- 400.0 91.9 3.40benzylamino)-ethyl]-phenoxy}- nicotinamide 1076-{4-[2-(Cyclopropylmethyl- 312.1 90.0 2.14 amino)-ethyl]-phenoxy}-nicotinamide 108 6-(4-{2-[(Naphthalen-1-ylmethyl)- 398.1 92.0 6.42amino]-ethyl}-phenoxy)- nicotinamide 1096-(4-{2-[(Bicyclo[2.2.1]hept-5-en- 364.1 97.5 4.632-ylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 1106-(4-{2-[(Naphthalen-2-ylmethyl)- 398.1 61.2 7.30amino]-ethyl}-phenoxy)- nicotinamide 111 6-(4-{2-[(Quinolin-4-ylmethyl)-399.1 55.3 1.54 amino]-ethyl}-phenoxy)- nicotinamide 1126-{4-[2-(2,6-Dichloro- 416.0 72.3 4.39 benzylamino)-ethyl]-phenoxy}-nicotinamide 113 6-{4-[2-(Indan-1-ylamino)-ethyl]- 374.1 96.0 4.23phenoxy}-nicotinamide 114 6-{4-[2-(2-Hydroxy-5-methoxy- 394.1 94.8 2.81benzylamino)-ethyl]-phenoxy}- nicotinamide 1156-{4-[2-(3-Bromo-4-fluoro- 446.0 93.9 5.97 benzylamino)-ethyl]-phenoxy}-nicotinamide 116 6-{4-[2-(4-Fluoro-2- 434.1 97.7 6.18trifluoromethyl-benzylamino)- ethyl]-phenoxy}-nicotinamide 1176-{4-[2-(3-Chloro-4-fluoro- 400.0 92.0 5.36benzylamino)-ethyl]-phenoxy}- nicotinamide 1186-[4-(2-Cyclooctylamino-ethyl)- 368.2 90.5 5.97 phenoxy]-nicotinamide119 6-{4-[2-(2-Phenoxy- 440.1 93.3 8.09 benzylamino)-ethyl]-phenoxy}-nicotinamide

By the method of example 35 the following compounds were prepared:

Mass Spectrum (ion spray) Example Name m/z (M + 1) ¹H NMR (CDCl₃) 1206-{4-[2-(Cyclobutylmethyl- 326.1 8.58(d, 1H), 8.16(dd, 1H),amino)-ethyl]-phenoxy}- 7.27-7.25(m, 4H), 7.07(d, 2H), nicotinamide6.96(d, 1H), 2.90-2.82(m, 4H), 2.67(d, 2H), 2.48-2.42(m, 1H),2.06-1.61(m, 7H) 121 6-{4-[2- 368.2 8.58(d, 1H), 8.16(dd, 1H),(Cycloheptylmethyl-amino)- 7.27-7.24(m, 4H), 7.09-7.06(m,ethyl]-phenoxy}- 2H), 6.99-6.94(m, 1H), nicotinamide 2.96-2.75(m, 4H),2.49(d, 2H), 1.74-1.12(m, 14H) 122 6-(4-{2-[(2-Morpholin-4-yl- 440.18.57(d, 1H), 8.16(dd, 1H), thiazol-5-ylmethyl)-amino]- 7.26-7.24(m, 4H),7.07(d, 2H), ethyl}-phenoxy)- 6.99-6.95(m, 2H), 3.86(s, 2H),nicotinamide 3.82-3.79(m, 4H), 3.44-3.42(m, 4H), 2.92(t, 2H), 2.82(t,2H), 1.25(s, 1H) 123 6-(4-{2-[(2,4-Dichloro- 423.0 8.57(d, 1H),8.19-8.15(m, 1H), thiazol-5-ylmethyl)-amino]- 7.27-7.24(m, 4H),7.11-7.07(m, ethyl}-phenoxy)- 2H), 6.99-6.96(m, 1H), 3.91(s,nicotinamide 2H), 2.98-2.93(m, 2H), 2.84-2.81(m, 2H), 1.64(br s, 1H) 1246-(4-{2-[(2-Chloro-thiazol- 389.0 8.57(d, 1H), 8.17(dd, 1H),5-ylmethyl)-amino]-ethyl}- 7.34(s, 1H), 7.26-7.24(m, 4H),phenoxy)-nicotinamide 7.09-7.07(m, 2H), 6.97(d, 1H), 3.94(d, 2H),2.93(t, 2H), 2.82(t, 2H), 1.55(br s, 1H) 125 6-{4-[2- 340.1 8.58(d, 1H),8.16(dd, 1H), (Cyclopentylmethyl-amino)- 7.27-7.24(m, 4H), 7.09-7.05(m,ethyl]-phenoxy}- 2H), 6.95(d, 1H), 2.92-2.81(m, nicotinamide 4H),2.57(d, 2H), 2.04-1.96(m, 1H), 1.78-1.48(m, 7H), 1.16-1.08(m, 2H)

Preparing Aldehyde Intermediates 4-Cyclohexyl-butyraldehyde

Add Dess-Martin reagent (7.02 g, 16.6 mmol) to a stirred solution of4-cyclohexyl-1-butanol (2.5 mL, 14.4 mmol) in anhydrous dichloromethane(120 mL). Stir for 3 h at room temperature under nitrogen. Add diethylether (200 mL) and 1N sodium hydroxide (150 mL) and stir for 10 minutes.Separate the layers and extract a second time with diethyl ether (100mL). Combine the diethyl ether extracts, wash with 1N sodium hydroxide(100 mL), dry over magnesium sulfate, filter, and concentrate on arotary evaporator to yield 2.01 g (90%) of 4-cyclohexyl-butyraldehyde:¹H NMR (CDCl₃): 9.76 (s, 1H), 2.41-2.37 (m, 2H), 1.71-1.58 (m, 7H),1.27-1.07 (m, 6H), 0.93-0.82 (m, 2H).

3-Cyclohexyl-propionaldehyde

Using a method similar alcohol oxidation method as above,3-cyclohexyl-1-propanol gives the title compound: ¹H NMR (CDCl₃): 9.76(s, 1H), 2.47-2.39 (m, 2H), 1.71-1.49 (m, 7H), 1.27-1.07 (m, 4H),0.93-0.84 (m, 2H).

Cyclohexyl-acetaldehyde

Using a similar the alcohol oxidation method as above, using2-cyclohexylethanol gives the title compound: ¹H NMR (CDCl₃): 9.75 (s,1H), 2.32-2.21 (m, 2H), 1.93-1.62 (m, 6H), 1.34-0.94 (m, 5H).

Cycloheptanecarbaldehyde

Using a similar alcohol oxidation method as above, cycloheptymethanolgives the title compound: ¹H NMR (CDCl₃): 9.63 (s, 1H), 2.39-2.33 (m,1H), 1.99-1.90 (m, 2H), 1.83-1.46 (m, 10H).

Cyclobutanecarbaldehyde

Using a similar alcohol oxidation method as above, usingcyclobutylmethanol gives the title compound: ¹H NMR (CDCl₃): 9.73 (s,1H), 3.20-3.14 (m, 1H), 2.32-1.86 (m, 6H).

Cyclopentanecarbaldehyde

Using a method as above, using cyclopentylmethanol gives the titlecompound: ¹H NMR (CDCl₃): 9.60 (s, 1H), 2.76-2.68 (m, 1H), 1.87-1.74 (m,4H), 1.65-1.54 (m, 4H).

EXAMPLE 1266-(4-{2-[(3,5-Dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide

Add sodium bicarbonate (0.0481 g, 0.573 mmol) to a stirred solution of4-(chloromethyl)-3,5-dimethylisoxazole (0.054 mL, 0.435 mmol), and6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1004 g, 0.390 mmol), indimethylformamide (4 mL). Heat the reaction to reflux under nitrogen for4 h. Cool to room temperature, pour the reaction mixture into 1 N sodiumhydroxide (50 mL), extract with diethyl ether (3×50 mL), dry theextracts over magnesium sulfate, filter, and concentrate on a rotaryevaporator to give the crude product. The crude product is purified byflash chromatography on silica gel eluting with 0.8% concentratedammonium hydroxide/8% ethanol/chloroform to yield 0.0843 g (59%) of6-(4-{2-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide:mass spectrum (ion spray): m/z=367.1 (M+1); ¹H NMR (CDCl₃): 8.57 (dd,1H), 8.16 (dd, 1H), 7.26-7.22 (m, 4H), 7.09-7.05 (m, 2H), 6.96 (d, 1H),3.54 (s, 2H), 2.88-2.79 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.50 (br s,1H).

By the method of example 126 the following compounds were prepared:

Example Name ¹H NMR (CDCl₃) 127 6-(4-{2-[(5-Methyl-isoxazol-3- 8.57(d,1H), 8.16(dd, 1H), 7.26-7.24(m, ylmethyl)-amino]-ethyl}- 4H),7.09-7.06(m, 2H), 6.96(d, 1H), 5.93(s, phenoxy)-nicotinamide 1H),3.84(s, 2H), 2.93(t, 2H), 2.83(t, 2H), 2.40(d, 3H), 1.59(br s, 1H) 1286-(4-{2-[(3-Phenyl-isoxazol-5- 8.56(d, 1H), 8.16(dd, 1H), 7.80-7.76(m,ylmethyl)-amino]-ethyl}- 2H), 7.46-7.42(m, 3H), 7.28-7.26(m, 4H),phenoxy)-nicotinamide 7.10-7.08(m, 2H), 6.96(d, 1H), 6.43(s, 1H),3.99(s, 2H), 2.99(t, 2H), 2.86(t, 2H), 1.61(br s, 1H) 1296-[4-(2-{[3-(4-Chloro-phenyl)- 8.56(d, 1H), 8.17(dd, 1H), 8.02(d, 2H),[1,2,4]oxadiazol-5-ylmethyl]- 7.46(d, 2H), 7.27-7.26(m, 3H), 7.09(d,2H), amino}-ethyl)-phenoxy]- 6.97(d, 2H), 4.14(s, 2H), 3.03-2.88(m, 4H),nicotinamide 1.59(br s, 1H) 130 6-(4-{2-[(5-p-Tolyl- 8.57(d, 1H),8.16(dd, 1H), 7.92(d, 2H), [1,3,4]oxadiazol-2-ylmethyl)- 7.31-7.25(m,6H), 7.08-7.06(m, 2H), amino]-ethyl}-phenoxy)- 6.95(d, 1H), 4.12(s, 2H),3.02(t, 2H), 2.87(t, nicotinamide 2H), 2.42(s, 3H), 1.65(br s, 1H) 1316-{4-[2-(1-Phenyl-ethylamino)- 8.57(d, 1H), 8.16(dd, 1H), 7.41-7.20(m,ethyl]-phenoxy}-nicotinamide 9H), 7.04(d, 2H), 6.95(d, 1H), 3.83-3.78(m,1H), 2.87-2.68(m, 4H), 1.65(br s, 1H), 1.36(d, 3H)

EXAMPLE 132 6-[4-(3-Benzylamino-propyl)-phenoxy]-nicotinamide

Step 1 N-Benzyl-3-(4-hydroxy-phenyl)-propionamide

Add benzylamine (32.0 mL, 293 mmol) to methyl3-(4-hydroxyphenyl)propionate (7.01 g, 38.9 mmol) and heat to 150° C.for 18 h under nitrogen. Cool to room temperature and pour the reactionmixture into 5 N hydrochloric acid (200 mL) and extract with ethylacetate (3×150 mL). Wash the ethyl acetate extracts with 5 Nhydrochloric acid (200 mL), dry the extracts over magnesium sulfate,filter, and concentrate on a rotary evaporator to yield 9.74 g (98%) ofN-benzyl-3-(4-hydroxy-phenyl)-propionamide: mass spectrum (ion spray):m/z=256.2 (M+1); ¹H NMR (DMSO-d₆): 9.15 (s, 1H), 8.28 (t, 1H), 7.39-6.96(m, 7H), 6.66-6.63 (m, 2H), 4.23 (d, 2H), 2.72 (t, 2H), 2.37 (t, 2H).

Step 2 4-(3-Benzylamino-propyl)-phenol

Add lithium aluminum hydride (8.00 g, 211 mmol) to anhydroustetrahydrofuran (150 mL) and cool to 0° C. under nitrogen. AddN-benzyl-3-(4-hydroxy-phenyl)-propionamide (9.74 g, 38.2 mmol) toanhydrous tetrahydrofuran (80 mL) and add this solution slowly viacannula to the lithium aluminum hydride/tetrahydrofuran mixture at 0° C.under nitrogen. Once this addition is complete, remove the ice bath andheat to reflux for 18 h under nitrogen. Cool the reaction to 0° C. andslowly quench with water (200 mL). Adjust the pH of the solution to pH=8with 4 M hydrochloric acid. Saturate this solution with sodium chloride,extract with ethyl acetate (3×100 mL), dry the extracts over magnesiumsulfate, filter, and concentrate on a rotary evaporator to yield 9.00 g(98%) of 4-(3-benzylamino-propyl)-phenol: mass spectrum (ion spray):m/z=242.1 (M+1); ¹H NMR (DMSO-d₆): 7.31-7.16 (m, 6H), 6.95-6.92 (m, 2H),6.66-6.62 (m, 2H), 3.65 (s, 2H), 2.48-2.43 (m, 5H), 1.68-1.60 (m, 2H).

Step 3

Using a method similar to example 1, step 2, using4-(3-benzylamino-propyl)-phenol and purifying by flash chromatography onsilica gel eluting with 1% concentrated ammonium hydroxide/10%ethanol/chloroform gives the title compound: HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 3.91 minutes, Purity: 98.9%; mass spectrum (ion spray):m/z=362.2 (M+1).

EXAMPLE 133 6-{4-[3-(Benzyl-pentyl-amino)-propyl]-phenoxy}-nicotinamide

Using a method similar to example 2, using6-[4-(3-benzylamino-propyl)-phenoxy]-nicotinamide (Step 3, Example 131)and 1-bromopentane gives the title compound: HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 8.40 minutes, Purity: 99.8%; mass spectrum (ion spray):m/z=432.3 (M+1).

By the method of example 132 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm × Mass 15 cm × 5 micron spectrum Retention Ex- (ionspray): Time ample Name m/z (M + 1) Purity (minutes) 1346-{4-[3-(Benzyl- 466.3 99.5 8.50 phenethyl-amino)-propyl]-phenoxy}-nicotinamide 134 6-(4-{3-[Benzyl-(3- 472.4 97.6 9.00cyclopentyl-propyl)- amino]-propyl}-phenoxy)- nicotinamide 1356-[4-(3-{Benzyl-[2-(3- 484.3 98.9 8.54 fluoro-phenyl)-ethyl]-amino}-propyl)-phenoxy]- nicotinamide

EXAMPLE 137 6-[4-(3-Pentylamino-propyl)-phenoxy]-nicotinamide

Using a method similar to example 132, adding pentyl amine to3-(4-hydroxyphenyl)propionate affords the intermediateN-pentyl-3-(4-hydroxyphenyl)-propionate. TheN-pentyl-3-(4-hydroxyphenyl)-propionate is reduced and displaced with6-chloronicotinamide to form the desired product. HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 4.77 minutes, Purity: 99.5%; mass spectrum (ion spray):m/z=342.3 (M+1).

By the method of example 137 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm × Mass 15 cm × 5 micron spectrum Retention (ion spray):Time Example Name m/z (M + 1) Purity (minutes) 138 6-[4-(3- 376.3 1005.94 Phenethylamino- propyl)-phenoxy]- nicotinamide 139 6-{4-[3-(3-382.3 97.5 8.20 Cyclopentyl- propylamino)-propyl]- phenoxy}-nicotinamide 140 6-(4-{3-[2-(3-Fluoro- 394.2 99.9 7.02phenyl)-ethylamino]- propyl}-phenoxy)- nicotinamide

EXAMPLE 141 (R)-6-[4-(2-Benzylamino-propyl)-phenoxy]-nicotinamide

Using a method similar to example 2, using(R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide givesthe title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) ZorbaxSB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.46 minutes,Purity: 97.9%; mass spectrum (ion spray): m/z=362.2 (M+1).

EXAMPLE 142 (R)-6-[4-(2-Dibenzylaino-propyl)-phenoxy]-nicotinamide

Using a method similar to example 2, using(R)-6-[4-(2-amino-pronyl)-pbenoxy]-nicotinamide and benzyl bromide givesthe title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) ZorbaxSB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.04 minutes,Purity: 99.8%; mass spectrum (ion spray): m/z=452.4 (M+1).

EXAMPLE 143 6-[4-(2-Benzylamino-2-methyl-propyl)-pbenoxy]-nicotinamide

Using a method similar to example 2, using6-[4-(2-amino-2-methyl-pronyl)phenoxy]-nicotinamide and benzyl bromidegives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water)Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.96minutes, Purity: 100%; mass spectrum (ion spray): m/z=376.2 (M+1).

By the method of example 142 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm × Mass 15 cm × 5 micron Ex- spectrum Retention am- (ionspray): Time ple Name m/z (M + 1) Purity (minutes) 144 6-[4-(2-Methyl-2-356.3 99.7 5.46 pentylamino-propyl)- phenoxy]-nicotinamide 1456-[4-(2-Methyl-2- 390.3 97.5 6.94 phenethylamino-propyl)-phenoxy]-nicotinamide 146 6-(4-{2-[2-(3-Fluoro- 408.2 98.2 7.63phenyl)-ethylamino]-2- methyl-propyl}-phenoxy)- nicotinamide 1476-{4-[2-(3-Cyclopentyl- 396.3 96.6 8.23 propylamino)-2-methyl-propyl]-phenoxy}- nicotinamide

EXAMPLE 148 (±)-6-[4-(3-Benzylamino-butyl)-phenoxy]-nicotinamide

Step 1 6-[4-(3-Oxo-butyl)-phenoxy]-nicotinamide

Add potassium carbonate (6.31 g, 45.7 mmol) to a stirred solution of4-(4-hydroxyphenol)-2-butanone (3.00 g, 18.3 mmol), and6-chloronicotinamide (2.87 g, 18.3 mmol) in dimethylacetamide (60 mL)and isooctane (10 mL). Equip with a Dean-Stark trap and heat thereaction to reflux for 6 h under nitrogen. Cool the reaction mixture toroom temperature, filter off the solids, and concentrate the filtrate ona rotary evaporator to give the crude product. The crude product ispurified by flash chromatography on silica gel eluting with 0.7%concentrated ammonium hydroxide/7% ethanol/chloroform to yield 3.49 g(67%) of 6-[4-(3-oxo-butyl)-phenoxy]-nicotinamide: mass spectrum (ionspray): m/z=285.2 (M+1); ¹H NMR (CDCl₃): 8.58 (d, 1H), 8.16 (dd, 1H),7.26-7.22 (m, 4H), 7.07-7.04 (m, 2H), 6.95 (d, 1H), 2.93-2.90 (m, 2H),2.81-2.77 (m, 2H), 2.16 (s, 3H).

Step 2

Add sodium triacetoxyborohydride (0.2301 g, 1.086 mmol) to a stirredsolution of 6-[4-(3-oxo-butyl)-phenoxy]-nicotinamide (0.2051 g, 0.7214mmol), benzylamine (0.079 mL, 0.723 mmol), glacial acetic acid (0.045mL, 0.786 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18h at room temperature under nitrogen. Add methanol (1.5 mL) and load thereaction mixture directly onto a 2 g prepacked SCX cartridge. Wash thecartridge with methanol (100 mL) and elute the product off of thecartridge with 2 M ammonia in methanol (50 mL). Concentrate the eluanton a rotary evaporator to yield 0.1863 g (69%) of6-[4-(3-benzylamino-butyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 4.09 minutes, Purity: 99.9%; mass spectrum (ion spray):m/z=376.4 (M+1).

By the method of example 148 the following compounds were prepared:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm × Mass 15 cm × 5 micron Ex- spectrum Retention am- (ionspray): Time ple Name m/z (M + 1) Purity (minutes) 1496-[4-(3-Pentylamino-butyl)- 356.5 100.0 5.19 phenoxy]-nicotinamide 1506-[4-(3-Propylamino-butyl)- 328.3 82.8 2.52 phenoxy]-nicotinamide 1516-[4-(3-Methylamino-butyl)- 300.2 52.2 1.94 phenoxy]-nicotinamide 1526-[4-(3-Phenethylamino- 390.2 97.7 6.48 butyl)-phenoxy]-nicotinamide 1536-(4-{3-[2-(3-Fluoro-phenyl)- 408.5 100.0 7.69ethylamino]-butyl}-phenoxy)- nicotinamide 1546-(4-{3-[2-(3-Chloro-phenyl)- 424.1 99.9 8.01ethylamino]-butyl}-phenoxy)- nicotinamide 1556-(4-{3-[(Furan-2-ylmethyl)- 366.4 89.5 89.50 amino]-butyl}-phenoxy)-nicotinamide 156 6-{4-[3-(2-Thiophen-2-yl- 396.5 99.0 5.30ethylamino)-butyl]-phenoxy}- nicotinamide 1576-{4-[3-(Cyclopropylmethyl- 340.2 88.2 2.76 amino)-butyl]-phenoxy}-nicotinamide 158 6-{4-[3-(3-Trifluoromethyl- 444.2 99.3 7.95benzylamino)-butyl]- phenoxy}-nicotinamide 159 6-{4-[3-(4-Fluoro- 394.299.3 4.92 benzylamino)-butyl]- phenoxy}-nicotinamide 1606-{4-[3-(3-Fluoro- 394.4 99.7 5.03 benzylamino)-butyl]-phenoxy}-nicotinamide 161 6-[4-(3-Allylamino-butyl)- 326.2 72.6 2.40phenoxy]-nicotinamide 162 6-{4-[3-(4-Chloro- 410.1 92.7 6.78benzylamino)-butyl]- phenoxy}-nicotinamide 163 6-{4-[3-(4-Methoxy- 406.299.9 5.09 benzylamino)-butyl]- phenoxy}-nicotinamide 1646-{4-[3-(4-Trifluoromethyl- 444.2 54.8 7.95 benzylamino)-butyl]-phenoxy}-nicotinamide 165 6-{4-[3-(4-Trifluoromethoxy- 460.2 99.9 8.09benzylamino)-butyl]- phenoxy}-nicotinamide 1666-{4-[3-(3-Trifluoromethoxy- 460.1 100.0 8.09 benzylamino)-butyl]-phenoxy}-nicotinamide 167 (1R)-6-{4-[3-(1-Phenyl- 390.2 71.0 5.30ethylamino)-butyl]-phenoxy}- nicotinamide 168 (1S)-6-{4-[3-(1-Phenyl-390.2 69.3 5.26 ethylamino)-butyl]-phenoxy}- nicotinamide

EXAMPLE 169 6-[4-(2-Benzylamino-propyl)-phenoxy]-nicotinamide

Step 1 6-[4-(2-Oxo-propyl)-phenoxy]-nicotinamide

Using a method similar to example 148 Step 1, using4-hydroxypehnylacetone and purifying by flash chromatography on silicagel eluting with 0.5% concentrated ammonium hydroxide/5%ethanol/chloroform gives the title compound: mass spectrum (ion spray):m/z=271.2 (M+1); ¹H NMR (CDCl₃): 8.59 (d, 1H), 8.18 (dd, 1H), 7.27-7.24(m, 4H), 7.14-7.10 (m, 2H), 6.98 (d, 1H), 3.73 (s, 2H), 2.21 (s, 3H).

Step 2

Using a method similar to example 148 Step 2, using6-[4-(2-oxo-propyl)-phenoxy]-nicotinamide gives the title compound: massspectrum (ion spray): HPLC (30/70 to 90/10 ACN/(0.1% TFA in water)Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.47minutes, Purity: 99.5%; mass spectrum (ion spray): m/z=362.4 (M+1).

By the method of example 169 the following compounds were made:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm × Mass 15 cm × 5 micron spectrum Retention Ex- (ionspray): Time ample Name m/z (M + 1) Purity (minutes) 1706-[4-(2-Pentylamino- 342.2 99.4 4.67 propyl)-phenoxy]- nicotinamide 1716-[4-(2-Propylamino- 314.2 68.8 2.26 propyl)-phenoxy]- nicotinamide 1726-[4-(2-Methylamino- 286.1 59.4 1.54 propyl)-phenoxy]- nicotinamide 1736-[4-(2-Phenethylamino- 376.2 98.9 5.35 propyl)-phenoxy]- nicotinamide174 6-(4-{2-[2-(3-Fluoro- 394.2 98.6 6.14 phenyl)-ethylamino]-propyl}-phenoxy)- nicotinamide 175 6-(4-{2-[2-(3-Chloro- 410.1 52.4 7.63phenyl)-ethylamino]- propyl}-phenoxy)- nicotinamide 1766-(4-{2-[(Furan-2- 352.1 77.2 2.49 ylmethyl)-amino]-propyl}-phenoxy)-nicotinamide 177 6-{4-[2-(2-Thiophen-2-yl- 382.1 98.2 4.21ethylamino)-propyl]- phenoxy}-nicotinamide 178 6-{4-[2- 326.2 74.6 2.36(Cyclopropylmethyl- amino)-propyl]-phenoxy}- nicotinamide 1796-{4-[2-(3- 430.1 88.4 7.00 Trifluoromethyl- benzylamino}-propyl]-phenoxy)-nicotinamide 180 6-{4-[2-(4-Fluoro- 380.1 98.3 4.04benzylamino)-propyl]- phenoxy}-nicotinamide 181 6-{4-[2-(3-Fluoro- 380.196.8 3.81 benzylamino)-propyl]- phenoxy}-nicotinamide 1826-[4-(2-Allylamino- 312.2 60.4 2.09 propyl)-phenoxy]- nicotinamide 1836-{4-[2-(4-Chloro- 396.1 98.5 5.87 benzylamino)-propyl]-phenoxy}-nicotinamide 184 6-{4-[2-(4- 392.2 82.2 7.06 Trifluoromethyl-benzylamino)-propyl]- phenoxy}-nicotinamide 185 6-{4-[2-(4-Methoxy-430.1 98.3 4.18 benzylamino)-propyl]- phenoxy}-nicotinamide 1866-{4-[2-(4- 446.1 99.0 7.97 Trifluoromethoxy- benzylamino)-propyl]-phenoxy}-nicotinamide 187 6-{4-[2-(3- 446.1 100.0 7.93 Trifluoromethoxy-benzylamino)-propyl]- phenoxy}-nicotinamide 188 (1S)-6-{4-[2-(1-Phenyl-376.2 98.6 4.26 ethylamino)-propyl]- phenoxy}-nicotinamide 189(1R)-6-{4-[2-(1-Phenyl- 376.2 98.6 4.27 ethylamino)-propyl]-phenoxy}-nicotinamide

EXAMPLE 190 6-[4-(2-Benzylamino-1-methyl-ethyl)-phenoxy]-nicotinamide

Step 1 N-Benzyl-2-(4-hydroxy-phenyl)-propionamide

Using a method similar to example 132 Step 1, using(4-hydroxyphenyl)-2-propanoic acid gives the title compound: massspectrum (ion spray): m/z=256.0 (M+1); ¹H NMR (DMSO-d₆): 9.23 (s, 1H),8.36 (t, 1H), 7.29-7.05 (m, 7H), 6.72-6.67 (m, 2H), 3.57-3.51 (m, 1H),1.30 (d, 3H).

Step 2 4-(2-Benzylamino-1-methyl-ethyl)-phenol

Dissolve N-benzyl-2-(4-hydroxy-phenyl)-propionamide (13.25 g, 51.9 mmol)in anhydrous tetrahydrofuran (100 mL) and add via a cannula toborane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 300 mL, 300mmol) under nitrogen. Heat the reaction to reflux for 18 h undernitrogen. Cool the reaction to 0° C. and quench with 6 M hydrochloricacid. Concentrate the tetrahydrofuran on a rotary evaporator to give thecrude product. Add water (50 mL) and tetrahydrofuran (30 mL) to thecrude product and heat the reaction to reflux for 1 h. Cool the reactionto room temperature and adjust the pH to pH=8 with 5 N sodium hydroxide.Add brine (200 mL) and extract with ethyl acetate (3×200 mL). Dry theethyl acetate extracts over magnesium sulfate, filter, and concentrateon a rotary evaporator to give the crude product. Purify the crudeproduct by flash chromatography on silica gel eluting with 0.7%concentrated ammonium hydroxide/7% ethanol/chloroform to yield 6.55 g(52%) of 4-(2-benzylamino-1-methyl-ethyl)-phenol: HPLC (30/70 to 90/10ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 3.08 minutes, Purity: 99.6%; mass spectrum (ion spray):m/z=242.1 (M+1).

Step 3

Using a method similar to example 1,4-(2-benzylamino-1-methyl-ethyl)-phenol is reacted with6-chloronicotinamide to afford the title compound. The crude product ispurified by flash chromatography on silica gel eluting with 0.7%concentrated ammonium hydroxide/7% ethanol/chloroform gives the titlecompound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-PhenylColumn 4.6 mm×15 cm×5 micron: Retention time: 4.52 minutes, Purity:99.1%; mass spectrum (ion spray): m/z=362.2 (M+1).

EXAMPLE 1916-{4-[2-(Benzyl-pentyl-amino)-1-methyl-ethyl]-phenoxy}-nicotinamide

Using a method similar to example 3, using6-[4-(2-benzylamino-1-methyl-ethyl)-phenoxy]-nicotinamide (example 190step 2), and 1-bromopentane gives the title product: HPLC (30/70 to90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5micron: Retention time: 8.52 minutes, Purity: 97.4%; mass spectrum (ionspray): m/z=432.3 (M+1).

EXAMPLE 192 6-[4-(1-Methyl-2-pentylamino-ethyl)-phenoxy]-nicotinamide

Using a method similar to example 22, using6-{4-[2-(benzyl-pentyl-amino)-1-methyl-ethyl]-phenoxy}-nicotinamidegives the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water)Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 5.31minutes. Purity: 100%; mass spectrum (ion spray): m/z=342.2 (M+1).

EXAMPLE 193 6-[4-(2-Amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide

Step 1 2-(4-Methoxy-phenyl)-2-methyl-propionitrile

Add potassium bis(trimethylsilyl)amide (39.90 g, 200 mmol) to a stirredsolution of 4-fluoroanisole (15.0 mL, 133 mmol), isobutyronitrile (49.0mL, 539 mmol) and anhydrous tetrahydrofuran (150 mL). Heat the reactionto reflux under nitrogen for 72 h. Cool the reaction to roomtemperature, pour it into 1 N hydrochloric acid (300 mL), and extractwith diethyl ether (3×100 mL). Wash the diethyl ether extracts withbrine (100 mL), dry the extracts over magnesium sulfate, filter, andconcentrate on a rotary evaporator to give the crude product. The crudeproduct is purified by flash chromatography on silica gel eluting with10% ethyl acetate/hexanes to yield 12.13 g (52%) of2-(4-methoxy-phenyl)-2-methyl-propionitrile: TLC: R_(f) in 10% ethylacetate/hexanes: 0.30; ¹H NMR (CDCl₃): 7.40-7.37 (m, 2H), 6.92-6.90 (m,2H), 3.81 (s, 3H), 1.70 (s, 6H).

Step 2 2-(4-Hydroxy-phenyl)-2-methyl-propionitrile

Add anhydrous dichloromethane (400 mL) to2-(4-methoxy-phenyl)-2-methyl-propionitrile (11.93 g, 68.1 mmol) andcool to −78° C. under nitrogen. Then add boron tribromide (33.0 mL, 349mmol) and stir at −78° C. for 30 minutes. Remove the dry ice/acetonebath and allow the reaction to warm to room temperature. Stir for 3 hand then pour the reaction onto ice. Extract with ethyl acetate (2×150mL), dry the extracts over magnesium sulfate, filter, and concentrate ona rotary evaporator to give the crude product. The crude product ispurified by flash chromatography on silica gel eluting with 35% ethylacetate/hexanes to yield 9.79 g (89%) of2-(4-hydroxy-phenyl)-2-methyl-propionitrile: TLC: R_(f) in 40% ethylacetate/hexanes: 0.38; ¹H NMR (CDCl₃): 7.34-7.32 (m, 2H), 6.86-6.83 (m,2H), 5.23 (s, 1H), 1.70 (s, 6H).

Step 3 [2-(4-Hydroxy-phenyl)-2-methyl-propyl]-carbamic acid tert-butylester

Add lithium aluminum hydride (10.00 g, 264 mmol) to anhydroustetrahydrofuran (250 mL) and cool the slurry to 0° C. Dissolve2-(4-hydroxy-phenyl)-2-methyl-propionitrile (9.90 g, 61.4 mmol) inanhydrous tetrahydrofuran (100 mL) and slowly, via cannula add thissolution to the above slurry at 0° C. under nitrogen. Allow the reactionto warm to room temperature and stir for 2 h under nitrogen. Then heatthe reaction to reflux. After 15 minutes cool the reaction to 0° C. andslowly quench with a saturated solution of ammonium chloride. Adjust thepH to pH=8 with 4 M hydrochloric acid and filter to remove the aluminumsalts. Add brine (300 mL) to the filtrate and extract with ethyl acetate(6×150 mL). Combine the ethyl acetate extracts and wash them with 1 Nhydrochloric acid (2×150 mL). Combine and adjust the pH of the 1 Nhydrochloric acid washes to pH=8 with sodium bicarbonate and thensaturate this solution with sodium bicarbonate. Then extract thesaturated sodium bicarbonate solution with ethyl acetate (5×150 mL) andwith chloroform (5×150 mL). Combine the organic extracts, dry withmagnesium sulfate, filter, and concentrate on a rotary evaporator toyield 2.78 g of the crude product. Add anhydrous tetrahydrofuran (150mL) to the crude product. Then add di-tert-butyl dicarbonate (5.00 g,22.9 mmol) to the reaction mixture and stir for 18 h at room temperatureunder nitrogen. Concentrate on a rotary evaporator to give the crudeproduct. The crude product is purified by flash chromatography on silicagel eluting with 25% ethyl acetate/hexanes to yield 0.86 g (5%) of[2-(4-hydroxy-phenyl)-2-methyl-propyl]-carbamic acid tert-butyl ester:mass spectrum (ion spray): m/z=266.1 (M+1); ¹H NMR (CDCl₃): 7.20 (d,2H), 6.80 (d, 2H), 4.31 (br s, 1H), 3.28 (d, 2H), 1.40 (s, 10H), 1.28(s, 6H).

Step 4{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamicacid tert-butyl ester

Add cesium carbonate (2.15 g, 6.60 mmol) to a stirred solution of[2-(4-hydroxy-phenyl)-2-methyl-propyl]-carbamic acid tert-butyl ester(0.86 g, 3.24 mmol) in dimethylformamide (20 mL). Stir for 30 minutesunder nitrogen at room temperature. Then add 6-chloronicotinamide (0.51g, 3.26 mmol) and heat to 100° C. under nitrogen for 6 h. Cool thereaction to room temperature, pour into brine (100 mL), extract withethyl acetate (3×75 mL), dry the ethyl acetate extracts over magnesiumsulfate, filter, and concentrate on a rotary evaporator to give thecrude product. The crude product is purified by flash chromatography onsilica gel eluting with 0.7% concentrated ammonium hydroxide/7%ethanol/chloroform to yield 0.5043 g (40%) of{2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamicacid tert-butyl ester: mass spectrum (ion spray): m/z=386.2 (M+1); ¹HNMR (CDCl₃): 8.64 (d, 1H), 8.20 (dd, 1H), 7.40 (d, 2H), 7.12 (d, 2H),6.98 (d, 1H), 4.38 (br s, 1H), 3.34 (d, 2H), 1.75 (br s, 2H), 1.41 (s,9H), 1.34 (s, 6H).

Step 5 6-[4-(2-Amino-1,1-dimethyl -ethyl)-phenoxy]-nicotinamide

Add trifluoroacetic acid (2.0 mL, 26.0 mmol) to a stirred solution of{2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamicacid tert-butyl ester (0.5000 g, 1.297 mmol) in dichloromethane (8 mL).Stir the reaction at room temperature under nitrogen for 2.5 h. Load thereaction contents directly onto a 10 g prepacked SCX cartridge, flushwith methanol (200 mL), and elute the product with 2 M ammonia inmethanol (75 mL). Concentrate the eluant on a rotary evaporator to givethe crude product. The crude product is purified by flash chromatographyon silica gel eluting with 1.5% concentrated ammonium hydroxide/15%ethanol/chloroform to yield 0.2626 g (71%) of6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide: mass spectrum(ion spray): m/z=286.1 (M+1); ¹H NMR (DMSO-d₆): 8.59 (d, 1H), 8.23 (dd,1H), 8.01 (s, 1H), 7.46 (s, 1H), 7.40-7.36 (m, 2H), 7.08-7.02 (m, 3H),3.32 (br s, 2H), 2.64 (s, 2H), 1.22 (s, 6H).

EXAMPLE 1946-[4-(2-Benzylamino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide

Using a method similar to example 35, using6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide (example 193),and benzaldehyde affords the title compound: HPLC (5/95 to 95/5ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron:Retention time: 6.01 minutes, Purity: 95.6%; mass spectrum (ion spray):m/z=376.1 (M+1).

By the method of example 194 the following compounds were prepared:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column4.6 mm × Mass 15 cm × 5 micron spectrum Retention Ex- (ion spray): Timeample Name m/z (M + 1) Purity (minutes) 195 6-{4-[2-(Cyclohexylmethyl-382.1 90.7 6.16 amino)-1,1-dimethyl-ethyl]- phenoxy}-nicotinamide 1966-{4-[2-(2-Chloro- 410.0 95.5 6.08 benzylamino)-1,1-dimethyl-ethyl]-phenoxy}- nicotinamide 197 6-{4-[2-(3-Fluoro- 394.1 97.5 6.04benzylamino)-1,1-dimethyl- ethyl]-phenoxy}- nicotinamide

EXAMPLE 198 6-[4-(3-Phenylamino-propyl)-phenoxy]-nicotinamide

Step 1 6-[4-(3-Hydroxy-propyl)-phenoxy]-nicotinamide

Add potassium carbonate (2.2821 g, 16.51 mmol) to a stirred solution of3-(4-hydroxyphenyl)-1-propanol (1.0041 g, 6.598 mmol),6-chloronicotinamide (1.0038 g, 6.411 mmol), dimethylacetamide (21 mL),and isooctane (3 mL). Equip the reaction setup with a Dean-Stark trapand heat the reaction to reflux under nitrogen for 6 h. Cool thereaction to room temperature and filter off the solids. Concentrate on arotary evaporator to give the crude product. Take the crude product upin 1 N sodium hydroxide (250 mL), extract with ethyl acetate (4×100 mL),dry the extracts over magnesium sulfate, filter, and concentrate on arotary evaporator to give the crude product. The crude product ispurified by flash chromatography on silica gel eluting with 1.5%concentrated ammonium hydroxide/15% ethanol/chloroform to yield 1.5188 g(87%) of 6-[4-(3-hydroxy-propyl)-phenoxy]-nicotinamide: mass spectrum(ion spray): m/z=273.2 (M+1); ¹H NMR (DMSO-d₆): 8.61 (d, 1H), 8.24 (dd,1H), 8.03 (s, 1H), 7.48 (s, 1H), 7.25 (d, 2H), 7.07-7.03 (m, 3H), 4.50(t, 1H), 3.46-3.41 (m, 2H), 2.63 (t, 2H), 1.77-1.70 (m, 2H).

Step 2 6-[4-(3-Oxo-propyl)-phenoxy]-nicotinamide

Add 6-[4-(3-hydroxy-propyl)-phenoxy]-nicotinamide (0.4051 g, 1.488 mmol)to a stirred solution of triethylamine (0.620 mL, 4.45 mmol) andanhydrous dimethylsulfoxide (4.5 mL). Dissolve pyridine sulfur trioxide(0.7023 g, 4.413 mmol) in anhydrous dimethylsulfoxide (4.5 mL) and addthis solution via a cannula to the above stirred solution undernitrogen. Stir the reaction at room temperature for 1 h under nitrogen.Pour the reaction into ice water (50 mL), extract with ethyl acetate(3×50 mL), dry the ethyl acetate extracts over magnesium sulfate,filter, and concentrate on a rotary evaporator to give the crudeproduct. The crude product is purified by flash chromatography on silicagel eluting with 100% ethyl acetate to yield 0.1428 g (36%) of6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray):m/z=271.2 (M+1); ¹H NMR (CDCl₃): 9.84 (t, 1H), 8.58 (d, 1H), 8.16 (dd,1H), 7.26-7.23 (m, 2H), 7.09-7.05 (m, 2H), 6.95 (d, 1H), 6.02 (br s,2H), 2.98 (t, 2H), 2.82 (t, 2H).

Step 3

Add sodium triacetoxyborohydride (0.1633 g, 0.7705 mmol) to a stirredsolution of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide (0.1341 g, 0.4962mmol), aniline (0.047 mL, 0.5158 mmol), and 1,2-dichloroethane (7 mL).Stir the reaction for 18 h at room temperature under nitrogen. Pour thereaction mixture into 1 N sodium hydroxide (50 mL), extract withdichloromethane (3×50 mL), dry the dichloromethane extracts overmagnesium sulfate, filter, and concentrate on a rotary evaporator togive the crude product. The crude product is purified by flashchromatography on silica gel eluting with 0.6% concentrated ammoniumhydroxide/6% ethanol/chloroform to yield 0.0142 g (8%) of6-[4-(3-phenylamino-propyl)-phenoxy]-nicotinamide: mass spectrum (ionspray): m/z=348.1 (M+1); ¹H NMR (CDCl₃): 8.58 (d, 1H), 8.16 (dd, 1H),7.26-7.18 (m, 7H), 7.10-7.04 (m, 2H), 6.97-6.94 (m, 1H), 6.79-6.51 (m,2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.04-1.97 (m, 3H).

EXAMPLE 199 6-[4-(2-Dimethylamino-ethyl)-phenoxy]-nicotinamide

Combine amine (50 mg, 0.19 mmol) from Example 34, and formaldehyde 38%(260 μL, 3.1 mmol) in MeOH (1 mL). Stir the mixture at room temperaturefor 2 hours. Add NaBH₄ (60 mg, 1.55 mmol) and stir overnight. Evaporatethe solvent in the rotatory evaporator, dissolve the crude product inCH₂Cl₂ and wash with H₂O. Extract the aqueous layer with CH₂Cl₂. Combineorganic layers and dry over MgSO₄. Eliminate the solvent and purify byflash chromatography on silica gel (eluent: CHCl₃/10% EtOH/1% NH₄OH) togive the title compound (32 mg, 58%). Electrospray MS M+1 ion=286,¹H-NMR (methanol-d₄, 300 MHz): 8.62 (d, 1H, J=2.5 Hz), 8.23 (dd, 1H,J=2.5 and 8.7 Hz), 7.31-7.27 (m, 2H), 7.08-7.04 (m, 2H), 6.96 (d, 1H,J=8.5 Hz), 2.86-2.78 (m, 2H), 2.61-2.54 (m, 2H), 2.32 (s, 6H).

EXAMPLE 200 6-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-nicotinamide

Step 1 6-[4-(2-Hydroxy-ethyl)-phenoxy]-nicotinamide

Combine 4-(2-hydroxy-ethyl)-phenol (2.0 g, 14.5 mmol),6-chloronicotinamide (2.3 g, 14.5 mmol) and K₂CO₃ (5.0 g, 36.2 mmol) inDMF (40 mL) under nitrogen, stir and heat at 120° C. overnight. Cool toambient temperature and pour into water, extract the aqueous layer withethyl acetate. Combine the organic layers and dry over Na₂SO₄. Eliminatethe solvent and purify by flash chromatography on silica gel (eluent:CHCl₃/7% EtOH/0.7% NH₄OH) to give the title compound (1.8 g, 49%).Electrospray MS M+1 ion=259, ¹H-NMR (DMSO-d₆, 400 MHz): 8.58 (d, 1H,J=2.7 Hz), 8.22 (dd, 1H, J=2.7 and 8.8 Hz), 8.00 (bs, 1H), 7.46 (bs,1H), 7.25 (m, 2H), 7.05-7.02 (m, 3H), 4.65 (t, 1H), J=5.3 Hz), 3.63-3.58(m, 2H), 2.72 (t, 2H, J=6.9 Hz).

Step 2

Dissolve 6-[4-(2-hydroxy-ethyl)-phenoxy]-nicotinamide (100 mg, 0.38mmol) under N₂ atmosphere in dry DMF (4 mL). Add Et₃N (108 μL, 0.77mmol) then cool the mixture at 0° C., add MsCl (29 μL, 0.38 mmol), allowthe mixture to warm to room temperature. After 1 hour add piperidine (76μL, 0.77 mmol) and heat the mixture at 90° C. for 1 hour. Cool toambient temperature and pour into water. Extract the aqueous layer withEtOAc. Dry the organic layer over MgSO₄. Eliminate the solvent. Purifyby flash chromatography on silica gel (eluent: CHCl₃/5% EtOH/0.5% NH₄OH)to give the title compound (65 mg, 55%). Electrospray MS M+1 ion=326,¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4 and8.5 Hz), 7.25-7.23 (m, 2H), 7.07-7.03 (m, 2H), 6.93 (d, 1H, J=8.5 Hz),6.12 (bs, 2H), 2.88-2.80 (m, 2H), 2.68-2.65 (m, 2H), 2.53-2.44 (m, 4H),1.67-1.59 (m, 4H), 1.51-1.43 (m, 2H).

By the method of example 200 the following compounds (examples 201-209)were prepared. All samples were purified following the same proceduredescribed for example 200 except where noted.

EXAMPLE 201 6-[4-(2-Morpholin-1-yl-ethyl)-phenoxy]-nicotinamide

Electrospray MS M+1 ion=328, ¹H-NMR (CDCl₃, 400 MHz): 8.51 (d, 1H, J=2.4Hz), 8.09 (dd, 1H, J=2.4 and 8.8 Hz), 7.21-7.17 (m, 2H), 7.02-6.98 (m,2H), 6.88 (d, 1H, J=8.8 Hz), 5.91 (bs, 2H), 3.72-3.67 (m, 4H), 2.80-2.74(m, 2H), 2.61-2.54 (m, 2H), 2.52-2.45 (m, 4H).

EXAMPLE 2026-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=374, ¹H-NMR (CDCl₃, 400 MHz): 8.52 (d, 1H, J=2.4Hz), 8.10 (dd, 1H, J=2.4 and 8.8 Hz), 7.25-7.22 (m, 2H), 7.10-6.97 (m,6H), 6.89 (d, 1H, J=8.8 Hz), 3.74 (bs, 2H), 2.96-2.76 (m, 8H).

EXAMPLE 2036-{4-[2-(4-Benzoyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=430, ¹H-NMR (CDCl₃, 400 MHz): 8.52 (d, 1H, J=2.4Hz), 8.10 (dd, 1H, J=2.4 and 8.5 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.52-7.47(m, 1H), 7.43-7.38 (m, 2H), 7.22-7.19 (m, 2H), 7.01-6.98 (m, 2H), 6.89(d, 1H, J=8.5 Hz), 3.22 (m, 1H), 3.07-3.00 (m, 2H), 2.82-2.76 (m, 2H),2.63-2.56 (m, 2H), 2.19-2.09 (m, 2H), 1.88-1.79 (m, 4H).

EXAMPLE 2046-{4-[2-(3-Methyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=340, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.3Hz), 8.16 (dd, H, J=2.4 and 8.2 Hz), 7.26-7.24 (m, 2H), 7.07-7.03 (m,2H), 6.95 (d, 1H, J=8.2 Hz), 3.48 (d, 1H, J=6.3 Hz), 3.00-2.81 (m, 4H),2.62-2.57 (m, 2H), 1.96-1.87 (m, 1H), 1.75-1.60 (m, 5H), 0.88 (d, 3H,J=6.3 Hz).

EXAMPLE 2056-{4-[2-(3,5-Dimethyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=354, ¹H-NMR (metanol-d₄, 400 MHz): 8.61 (d, 1H,J=2.7 Hz), 8.24 (dd, 1H, J=2.7 and 8.5 Hz), 7.32-7.28 (m, 2H), 7.08-7.05(m, 2H), 6.96 (d, 1H, J=8.5 Hz), 3.02-2.98 (m, 2H), 2.90-2.84 (m, 2H),2.67-2.61 (m, 2H), 1.80-1.59 (m, 6H), 0.91 (t, 6H, J=6.5 Hz).

EXAMPLE 2066-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide

Purification: 5-95% gradient 3 ml/min (ACN&H₂O with 6.5 nM NH₄OAc) on a4.6×50 mm Symmetry Column. Electrospray MS M+1 ion=492, ¹H-NMR(methanol-d₄, 400 MHz): 8.61 (d, 1H, J=2.5 Hz), 8.23 (dd, 1H, J=2.5 and8.9 Hz), 7.34-7.22 (m, 10H), 7.15-7.10 (m, 2H), 7.06-7.03 (m, 2H), 6.95(d, 1H, J=8.9 Hz), 3.53 (d, 1H, J=10.3 Hz), 3.07-3.02 (m, 2H), 2.87-2.82(m, 2H), 2.68-2.63 (m, 2H), 2.31-2.13 (m, 3H), 1.62-1.57 (m, 2H),1.32-1.22 (m, 2H).

EXAMPLE 2076-{4-[2-(4-Phenyl-piperidin-1-yl)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=402, ¹H-NMR (CDCl₃, 400 MHz): 8.51 (d, 1H, J=2.4Hz), 8.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.27-7.11 (m, 7H), 7.02-6.99 (m,2H), 6.89 (d, 1H, J=8.7 Hz), 3.13-3.07 (m, 2H), 2.86-2.79 (m, 2H),2.64-2.57 (m, 2H), 2.52-2.41 (m, 1H), 2.14-2.05 (m, 2H), 1.84-1.75 (m,4H).

EXAMPLE 2086-(4-{2-[3-Fluoro-phenyl)-piperidin-1-yl)-ethyl}-phenoxy]-nicotinamide

Purification: 5-95% gradient 3 ml/min (ACN&H₂O with 6.5 nM NH₄OAc) on a4.6×50 mm Symmetry Column. Electrospray MS M+1 ion=420, ¹H-NMR(methanol-d₄, 400 MHz): 8.61 (d, 1H, J=2.4 Hz), 8.23 (dd, 1H, J=2.4 and8.6 Hz), 7.33-7.26 (m, 4H), 7.09-7.00 (m, 4H), 6.96 (d, 1H, J=8.6 Hz),3.28-3.17 (m, 2H), 2.96-2.81 (m, 5H), 2.40-2.30 (m, 2H), 1.97-1.74 (m,3H), 1.63-1.52 (m, 1H).

EXAMPLE 209 6-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-nicotinamide

Electrospray MS M+1 ion=340, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.6Hz), 8.16 (dd, 1H, J=2.6 and 8.8 Hz), 7.26-7.23 (m, 2H), 7.07-7.03 (m,2H), 6.94 (d, 1H, J=8.8 Hz), 2.84-2.72 (m, 8H), 1.73-1.59 (m, 8H).

EXAMPLE 210 6-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide

Combine amine (65 mg, 0.20 mmol) from example 1, AcOH (70 μL, 1.2 mmol),formaldehyde (0.6 mmol) and NaBH(OAc)₃ (0.40 mmol) in 1,2-DCE (2 mL).Stir the mixture at room temperature overnight. Dilute the mixture withCH₂Cl₂ and wash with NaHCO₃ sat. Extract the aqueous layer with CH₂Cl₂,combine the organic layers and dry over Na₂SO₄. Purify by flashchromatography on silica gel (eluent: EtOAc). Electrospray MS M+1ion=362, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.6 Hz), 8.15 (dd, 1H,J=2.6 and 8.6 Hz), 7.32-7.22 (m, 7H), 7.06-7.04 (m, 2H), 6.95 (d, 1H,J=8.6 Hz), 3.61 (bs, 2H), 2.91-2.84 (m, 2H), 2.74-2.66 (m, 2H), 2.32 (s,3H).

By method of example 210 the following compounds were prepared: examples211-216.

EXAMPLE 211 6-{4-[2-(Benzyl-ethyl-amino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=376, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.5Hz), 8.14 (dd, 1H, J=2.5 and 8.7 Hz), 7.33-7.18 (m, 7H), 7.04-7.01 (m,2H), 6.92 (d, 1H, J=8.7 Hz), 6.17 (bs, 2H), 3.66 (s, 2H), 2.82-2.72 (m,4H), 2.62 (c, 2H, J=7.1 Hz), 1.08 (t, 3H, J=7.1 Hz).

EXAMPLE 212 6-{4-[2-(Benzyl-propyl-amino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=390, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.4Hz), 8.14 (dd, 1H, J=2.4 and 8.3 Hz), 7.35-7.15 (m, 7H), 7.14-7.00 (m,2H), 6.92 (d, 1H, J=8.3 Hz), 3.66 (bs, 2H), 2.82-2.69 (m, 4H), 2.49 (t,2H, J=7.1 Hz), 1.52 (m, 2H), 0.87 (t, 3H, J=7.1 Hz).

EXAMPLE 213 6-{4-[2-(Benzyl-butyl-amino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=404, ¹H-NMR (CDCl₃, 400 MHz): 8.58 (d, 1H, J=2.4Hz), 8.15 (dd, 1H, J=2.4 and 8.3 Hz), 7.35-7.16 (m, 7H), 7.05-7.00 (m,2H), 6.92 (d, 1H, J=8.3 Hz), 3.65 (bs, 2H), 2.83-2.68 (m, 4H), 2.52 (t,2H, J=7.1 Hz), 1.48 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H, J=7.1 Hz).

EXAMPLE 2146-{4-[2-(Benzyl-cyclopropylmethylamino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=402, ¹H-NMR (CDCl₃, 400 MHz): 8.47 (d, 1H, J=2.5Hz), 8.05 (dd, 1H, J=2.5 and 8.7 Hz), 7.27-7.07 (m, 7H), 6.96-6.91 (m,2H), 6.84 (d, 1H, J=8.7 Hz), 3.64 (bs, 2H), 2.72 (m, 4H), 2.34 (m, 2H),0.80 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H).

EXAMPLE 215 6-{4-[2-(Benzyl-isobutyl-amino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=404, ¹H-NMR (CDCl₃, 400 MHz): 8.57 (d, 1H, J=2.3Hz), 8.15 (dd, 1H, J=2.3 and 8.6 Hz), 7.34-7.15 (m, 7H), 7.04-6.99 (m,2H), 6.92 (d, 1H, J=8.6 Hz), 3.61 (s, 2H), 2.80-2.64 (m, 4H), 2.24 (d,2H, J=7.0 Hz), 1.78 (m, 1H), 0.87 (t, 6H, J=7.0 Hz).

EXAMPLE 2166-{4-[2-(Benzyl-(3-methyl-butyl)-amino)-ethyl]-phenoxy}-nicotinamide

Electrospray MS M+1 ion=418, ¹H-NMR (CDCl₃, 400 MHz): 8.51 (d, 1H, J=2.5Hz), 8.08 (dd, 1H, J=2.5 and 8.8 Hz), 7.26-7.15 (m, 5H), 7.13-7.10 (m,2H), 6.97-6.94 (m, 2H), 6.87 (d, 1H, J=8.8 Hz), 3.57 (s, 2H), 2.74-2.61(m, 4H), 2.46 (t, 2H, J=7.4 Hz), 1.56-1.46 (m, 1H), 1.31 (c, 2H, J=7.1Hz), 0.79 (d, 6H, J=7.1 Hz).

EXAMPLE 217 Synthesis of6-[4-(2-Benzoylamino-ethyl)-phenoxy]-nicotinamide

Combine amine starting material of Example 34 (100 mg, 0.39 mmol),benzoyl chloride (50 μL, 0.43 mmol) and Et₃N (120 μL, 0.86 mmol) in THF(4 mL) and DMF (0.5 mL). Stir the mixture at room temperature for 3hours. Eliminate the solvent and purify by flash chromatography onsilica gel (eluent: EtOAc/hexane 75/25) to give the title compound. (90mg, 65%). Electrospray MS M+1 ion=362, ¹H-NMR (methanol-d₄, 400 MHz):8.62 (d, 1H, J=2.8 Hz), 8.24 (dd, 1H, J=2.8 and 9.0 Hz), 7.79-7.76 (m,2H), 7.55-7.42 (m, 5H), 7.09-7.06 (m, 2H), 6.96 (d, 1H, J=9.0 Hz), 3.62(t, 2H, J=7.3 Hz), 2.95 (t, 2H, J=7.3 Hz).

Synthesis of 4-[4-(2-Benzylamino-ethyl)-phenoxy]-2-fluoro-benzamide(Example 218) and 2-[4-(2-Benzylamino-ethyl)-phenoxy]-4-fluoro-benzamide(Example 219) EXAMPLE 2184-[4-(2-Benzylamino-ethyl)-phenoxy]-2-fluoro-benzamide

Step 1 4-(2-Benzylamino-ethyl)-phenol

Combine tyramine (5.0 g, 36.4 mmol), benzaldehyde (3.8 ml, 37.2 mmol) inMeOH (46 mL), heat at reflux for 2 h. Cool the mixture at 0° C. and addNaBH₄ (1.44 g, 38.2 mmol). Stir at room temperature overnight. Removemost of MeOH, add H₂O and stir for 2 h. Filter the mixture and wash thewhite solid with water. Dry the solid precipitate under vacuum at 40° C.overnight to afford the title compound (7.53 g, 91%). Electrospray MSM+1 ion=228, ¹H-NMR (methanol-d₄, 300 MHz): 7.40-7.20 (m, 5H), 7.03-6.95(m, 2H), 6.73-6.65 (m, 2H), 3.75 (s, 2H), 2.85-2.65 (m, 4H).

Step 2 Benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butylester

Combine the product of step 1 (2.0 g, 8.8 mmol) and di-tert-butyldicarbonate (2.11 g, 9.6 mmol) in THF (120 mL), stir the mixture at roomtemperature overnight. Eliminate the solvent and purify on silica gel(eluent: gradient from hexane to hexane/EtOAc 20/80) to afford the titlecompound (2.0 g, 68%). Electrospray MS M−1 ion=326, ¹H-NMR (methanol-d₄,400 MHz): 7.34-7.15 (m, 5H), 7.05-6.90 (m, 2H), 6.75-6.65 (m, 2H),4.40-4.25 (m, 2H), 3.40-3.25 (m, 2H), 2.65-2.60 (m, 2H), 1.20 (s, 9H).

Step 3 Benzyl-{2-[4-(4-cyano-3-fluoro-phenoxy)-phenyl]-ethyl}-carbamicacid tert-butyl ester andBenzyl-{2-[4-(2-cyano-5-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester

Combine benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butylester (400 mg, 1.23 mmol) and K₂CO₃ (187 mg, 1.35 mmol) in DMF (6 mL),stir the mixture at room temperature for 30 min and then add2.4-difluoro-benzonitrile (188 mg, 1.35 mmol), heat at 100° C.overnight. Cool the mixture to about room temperature and pour it intowater. Extract the aqueous layer with EtOAc. Dry the organic layer overNa₂SO₄ and eliminate the solvent in the rotatory evaporator. Purify onsilica gel (eluent: EtOAc/hexanes 15/85) to get the mixture of bothregioisomers (400 mg, 73%). Electrospray MS M−1 ion=445, ¹H-NMR (CDCl₃,400 MHz, mixture of the two regioisomers): 7.36 (dd, 1H, J=5.3 and 8.2Hz), 7.51 (t, 1H, J=7.6 Hz), 7.36-7.13 (m, 17H), 7.01 (d, 1H, J=8.2 Hz),6.97 (d, 1H, J=8.2 Hz), 6.83-6.76 (m, 1H), 6.68 (d, 1H, J=10.0 Hz), 6.46(d, 1H, J=10.0 Hz), 4.46-4.34 (m, 4H), 3.48-3.32 (m, 4H), 2.88-2.73 (m,4H), 1.50-1.45 (m, 18H).

Step 4Benzyl-{2-[4-(2-carbamoyl-5-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester andbenzyl-{2-[4-(4-carbamoyl-3-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester

Combine benzyl-{2-[4-(4-cyano-3-fluoro-phenoxy)-phenyl]-ethyl}-carbamicacid tert-butyl ester andbenzyl-{2-[4-(2-cyano-5-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester, a mixture of both regioisomers, (100 mg, 0.22 mmol),H₂O₂ (26 μL), and K₂CO₃ (16 mg, 0.11 mmol) in DMSO (0.8 mL). Stir themixture at room temperature for 3 hours and add water. Extract theaqueous layer with EtOAc. Dry the organic layer over MgSO₄. Eliminatethe solvent and purify by flash chromatography (eluent: AcOEt/hexane40/60) to give the mixture of regioisomeric carboxamides (90 mg, 85%).The regioisomers were separated by HPLC (Kromasil silica column 10 umsilica particle size, 5 cm id*25 cm length. The elute system is 120mL/min 5/45/50 (IPA/DCM/hexanes), 30 mg loading in 100% DCM).

Step 5a

Kromasil silica column 46 id*25 cm length. The elute system is 1 mL/min5/45/50 (IPA/DCM/hexanes), retention time: 6.66 min. ¹H-NMR (CDCl₃, 300MHz): 8.27 (dd, 1H, J=6.9 and 8.9 Hz), 7.55 (bs, 1H), 7.37-7.13 (m, 7H),7.04-6.97 (m, 2H), 6.86 (t, 1H, J=8.2 Hz), 6.42 (d, 1H, J=10.3 Hz), 5.90(bs, 1H), 4.45-4.36 (m, 2H), 3.47-3.30 (m, 2H), 2.88-2.71 (m, 2H),1.53-1.41 (m, 9H).

Step 5b

Kromasil silica column 46 id*25 cm length. The elute system is 1 ml/min5/45/50 (IPA/DCM/HEXANE), retention time: 7.68 min. ¹H-NMR (CDCl₃, 400MHz): 8.00 (t, 1H, J=9.7 Hz), 7.30-7.04 (m, 7H), 6.94-6.90 (m, 2H), 6.75(dd, 1H, J=2.4 and 8.4 Hz), 6.58 (dd, 1H, J=2.4 and 13.9 Hz), 6.52 (m,1H), 5.69 (bs, 1H), 4.38-4.28 (m, 2H), 3.40-3.25 (m, 2H), 2.79-2.65 (m,2H), 1.45-1.35 (m, 9H).

Dissolve compound of step 5b (23 mg, 0.049 mmol) in CH₂Cl₂ (2 mL) andadd trifluoroacetic acid (99 μL, 1.29 mmol), stir the mixture at roomtemperature for 5 h. Eliminate the solvent and purify on a SCX column toafford the title compound (18 mg, 99%). Electrospray MS M+1 ion=365.¹H-NMR (CDCl₃, 400 MHz): 8.06 (t, 1H, J=8.4 Hz), 7.35-7.22 (m, 7H),7.01-6.98 (m, 2H), 6.82 (dd, 1H, J=2.4 and 8.9 Hz), 6.66 (dd, 1H, J=2.4and 13.6 Hz), 6.60 (bd, 1H), 6.00 (bd, 1H), 3.82 (s, 2H), 2.95-2.90 (m,2H), 2.87-2.82 (m, 2H).

EXAMPLE 219 2-[4-(2-Benzylamino-ethyl)-phenoxy]-4-fluoro-benzamide

The title compound was prepared from the compound of example 218 step 5afollowing the same acidic hydrolysis described above.

Electrospray MS M+1 ion=365. ¹H-NMR (CDCl₃, 400 MHz): 8.28 (dd, 1H,J=6.6 and 8.0 Hz), 7.55 (bs, 1H), 7.35-7.23 (m, 7H), 7.05-7.00 (m, 2H),6.86 (ddd, 1H, J=2.2, 8.0 and 10.0 Hz), 6.46 (dd, 1H, J=2.2 and 10.0Hz), 5.89 (bs, 1H), 3.83 (s, 2H), 2.95-2.90 (m, 2H), 2.88-2.83 (m, 2H).

EXAMPLE 220 4-[4-(2-Benzylamino-ethyl)-phenoxy]-2-chloro-benzamide

Step 1 Benzyl-{2-[4-(3-chloro-4-cyano-phenoxy)-phenyl]-ethyl}-carbamicacid tert-butyl ester

Combine the compound from Example 218 step 2 (692 mg, 2.12 mmol) andK₂CO₃ (323 mg, 2.33 mmol) in DMF (9 mL), stir the mixture at roomtemperature for 30 min and then add 2-chloro-4-fluoro-benzonitrile (330mg, 2.12 mmol), and heat at 100° C. overnight. Cool to ambienttemperature and pour into water. Extract the aqueous layer with EtOAc.Dry the organic layer over Na₂SO₄ and eliminate the solvent. Purify byflash chromatography on silica gel (eluent: EtOAc/hexane 15/85) toobtain the title compound (940 mg, 95%). Electrospray MS M−1 ion=461,¹H-NMR (CDCl₃, 400 MHz): 7.57 (d, 1H, J=7.8 Hz), 7.36-7.13 (m, 7H),7.00-6.85 (m, 4H), 4.44-4.36 (m, 2H), 3.49-3.32 (m, 2H), 2.83-2.73 (m,2H), 1.51-1.43 (m, 9H).

Step 2

Combine the compound of step 1 (95 mg, 0.21 mmol), H₂O₂ (25 μl) andK₂CO₃ (15 mg, 0.10 mmol) in DMSO (0.8 mL), and stir the mixture at roomtemperature overnight. Add water and extract the aqueous layer withEtOAc. Dry the organic layer over Na₂SO₄ and eliminate the solvent.Purify by flash chromatography (EtOAc/hexane 50/50) to give a yellowoil. Dissolve the oil in CH₂Cl₂ (3 mL) and add trifluoroacetic acid (240μL), and stir the mixture at room temperature for 4 hour. Eliminate thesolvent. Purify by an SCX column to give the title compound (57 mg,76%). Electrospray MS M+1 ion=381. ¹H-NMR (CDCl₃, 400 MHz): 7.82 (d, 1H,J=8.5 Hz), 7.35-7.20 (m, 7H), 6.99-6.95 (m, 3H), 6.90 (dd, 1H, J=2.5 and8.5 Hz), 6.53 (m, 2H), 3.83 (s, 2H), 2.95-2.89 (m, 2H), 2.86-2.81 (m,2H).

EXAMPLE 221 6-[4-(2-Benzylamino-ethyl)-2-methyl-phenoxy]-nicotinamide

Step 1 6-(4-Formyl-2-methyl-phenoxy)-nicotinonitrile

Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K₂CO₃ (570mg, 4.12 mmol) and 6-chloronicotinonitrile (408 mg, 2.94 mmol) in DMF (6ml), heat at 100° C. After 4 h cool to ambient temperature and pour intowater. Extract the aqueous layer with EtOAc. Dry the organic layer overNa₂SO₄ and eliminate the solvent. Dry under vacuum at 45° C. overnightto get the title compound (680 mg, 97%). ¹H-NMR (CDCl₃, 400 MHz): 9.99(s, 1H), 8.43 (d, 1H, J=2.5 Hz), 7.97 (dd, 1H, J=2.5 and 8.8 Hz), 7.84(bs, 1H), 7.80 (dd, 1H, J=2.5 and 8.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.11(d, 1H, J=8.4 Hz), 2.24 (s, 3H).

Step 2 6-[4-(2-Methoxy-vinyl)-2-methyl-phenoxy]-nicotinonitrile

Suspend (methoxymethyl)triphenylphosphonium chloride (1.14 g, 3.34mmol)in THF (11 mL) under N₂ and cool the mixture at 0° C., add slowly0.5M KHMDS in toluene (6.7 mL, 3.34 mmol) and stir at 0° C. for 30 min.Cool the mixture at −78° C. and add a solution of aldehyde from step 1above (663 mg, 2.78 mmol) in THF (2 mL). Wann the mixture slowly to roomtemperature, and stir for 1 h. Add water and extract the aqueous layerwith Et₂O. Dry the organic layer over MgSO₄. Eliminate the solvent andpurify by flash chromatography on silica gel (eluent: gradient fromEtOAc/hexane 10/90 to 20/80) to get the title compound (530 mg, 76%).Electrospray MS M+1 ion=267. ¹H-NMR (CDCl₃, 300 MHz, mixture ofisomers): 8.47-8.45 (m, 2H), 7.92-7.86 (m, 2H), 7.50-7.45 (m, 1H),7.15-6.93 (m, 8H), 6.14 (d, 1H, J=7.1 Hz), 5.79 (d, 1H, J=13.2 Hz), 5.20(d, 1H, J=7.1 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 2.11 (s, 3H), 2.10 (s,3H).

Step 3 6-[4-(2-Benzylamino-ethyl)-2-methyl-phenoxy]-nicotinonitrile

Combine the compound of example 221, step 2(6-[4-(2-methoxy-vinyl)-2-methyl-phenoxy]-nicotinamide) (125 mg, 0.50mmol) and p-TsOH (9 mg, 0.05 mmol) in i-PrOH (0.7 mL) and H₂O (0.7 mL).Heat the mixture at reflux for 4 hours. Cool the reaction mixture toabout room temperature. Add NaHCO₃ (sat) and extract the aqueous layerwith Et₂O. Dry the organic layer over MgSO₄ to afford an oil (120 mg).Dissolve the oil (66 mg) in 1,2-DCE (3.2 mL) and add benzylamine (40μL), AcOH (97 μL) and NaBH(OAc)₃ (119 mg), stir the mixture at roomtemperature overnight. Dilute with CH₂Cl₂ and add saturated NaHCO3,extract the aqueous layer with CH₂Cl₂, combine organic layers and dryover Na₂SO₄. Eliminate the solvent and purify by flash chromatography onsilica gel (eluent: EtOAc/hexane 75/25) to afford the title compound (16mg). Electrospray MS M+1 ion=344. ¹H-NMR (CDCl₃, 400 MHz): 8.45 (d, 1H,J=2.5 Hz), 7.89 (dd, 1H, J=2.5 and 8.9 Hz), 7.35-7.23 (m, 5H), 7.13-7.07(m, 2H), 7.00-6.94 (m, 2H), 3.82 (s, 2H), 2.92 (t, 2H, J=7.4 Hz), 2.82(t, 2H, J=7.4 Hz),

Step 4

Combine nitrile,6-[4-(2-benzylamino-ethyl)-2-methyl-phenoxy]-nicotinonitrile (compoundof example 219, step 3) (13 mg, 0.04 mmol), H₂O₂ (5 μL) and K₂CO₃ (3 mg,0.02 mmol) in DMSO (0.2 mL), and stir the mixture at room temperatureovernight. Add water and extract the aqueous layer with EtOAc. Dry theorganic layer over Na₂SO₄ and eliminate the solvent. Purify by flashchromatography (eluent: CHCl₃/0.5% EtOH/0.05% NH₄OH) to give the titlecompound (7 mg, 52%). Electrospray MS M+1 ion=362. ¹H-NMR (methanol-d₄,300 MHz): 8.59 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J=2.5 and 8.0 Hz),7.33-7.21 (m, 5H), 7.15-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.78 (s, 2H),2.83 (s, 4H), 2.09 (s, 3H).

EXAMPLE 222 Synthesis of6-[2-Methyl-4-(phenethylamino-methyl)-pbenoxy]nicotinamide

Step 1 Synthesis of 6-(4-Formyl-2-methyl-phenoxy)-nicotinamide

A solution of 4-hydroxy-3-methylbenzaldehyde (1.0 equiv) in DMF (0.2 Msolution) was treated with K₂CO₃ (1.5 equiv) and 6-chloronicotinamide(1.0 equiv). The reaction mixture was placed inside the microwave ovenand then irradiated for 5 min. Upon completion of the reaction, themixture was cooled, poured into H₂O and extracted with ethyl acetate,and the combined organic layers were washed twice with water and brine.After drying the extracts over magnesium sulfate and evaporation undervacuum the crude product was purified by silica gel chromatography usingCHCl₃: EtOH 7%: NH₄OH 0.7% to afford the title compound as a solid.

40% yield

¹H NMR (CD₃OD, 200 MHz) δ: 9.94 (s, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.29(dd, J=8.8, 2.6 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J=8.4, 1.8 Hz, 1H),7.22 (d, J=8.4 Hz, 1Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 2.22 (s, 3H). ¹³CNMR (CD₃OD, 200 MHz) δ:191.6, 167.3, 165.3, 157.2, 147.6, 140.0, 134.1,133.4, 132.2, 129.5, 125.0, 122.7, 111.6, 16.8.

Step 2

A mixture of aldehyde from step 1 above (1 equiv), phenethylamine (1equiv), 4 A molecular sieves (10% weight) in methanol (0.1 M) wasstirred overnight under nitrogen atmosphere at room temperature. Thefollowing day NaBH₄ (5 equiv) was added and the reaction mixture wasstirred for 3 hours. The reaction can be monitored by electrospray MS.The reaction mixture was filtered off and the solvent evaporated toyield a residue, which was purified by SCX or flash chromatography.

99% yield

¹H NMR (CD₃OD, 200 MHz) δ:8.60 (d, J=2.7 Hz, 1H), 8.24 (dd, J=8.9, 2.7Hz, 1H), 7.30 (dd, J=8.6, 1.6 Hz, 2H), 7.27 (d, J=17.5 Hz, 3H), 7.22 (d,J=14.2 Hz, 3H), 7.02-6.93 (m, 2H), 3.77 (s, 2H), 2.85 (s, 4H), 2.12 (s,3H).

¹³C NMR (CD₃OD, 200MHz) δ: 168.2, 165.5, 150.7, 147.4, 139.5, 139.4,136.6, 131.2, 130.3, 128.2, 128.1, 127.1, 125.8, 124.3, 121.4, 109.7,52.2, 49.9, 35.2, 14.9. MS (APCI): (M⁺+1) 362.2.

EXAMPLE 223 Synthesis of6-[2-Fluoro-4-(phenethylamino-methyl)-phenoxy]nicotinamide

Step 1 Synthesis of 6-(2-Fluoro-4-formyl-phenoxy)-nicotinamide

Using a procedure similar to that of example 221 step 1, and using4-hydroxy-3-fluoro-benzaldehyde the above compound was prepared in 38%yield

¹H NMR (CDCl₃, 200 MHz) δ: 9.99 (s, 1H), 8.52 (d, J=1.9 Hz, 1H), 8.25(dd, J=8.6, 2.4 Hz, 1H), 7.76-7.71 (m, 2H), 7.47-7.40 (m, 1H), 7.14 (d,J=8.6 Hz, 1H). MS (Electrospray): (M⁺+1) 261.1.

Step 2

The compound of example 221 step 1 was reductively aminated withphenethylamine using procedures similarly to those previously describedto afford the title compound in 8% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (dd, J=2.4, 0.8 Hz, 1H), 8.27 (dd,J=8.6, 2.4 Hz, 1H), 7.32-7.14 (m, 9H), 7.08 (dd, J=8.6, 0.8 Hz, 1H),3.79 (s, 2H), 2.84 (s, 4H).

¹³C NMR (CD₃OD, 200 MHz) δ: 168.7, 165.3, 154.9 (d, ¹J_(CF)=246.5),147.6, 139.9, 139.8, 139.2 (d, ³J_(CF)=6.2), 128.7, 128.5, 127.1, 126.3,124.9 (d, ³J_(CF)=3.4), 123.9, 116.7 (d, ²J_(CF)=18.6), 110.3, 52.4,50.4, 35.8. MS (Electrospray): (M⁺+1) 366

EXAMPLE 224 Synthesis of6-[2-Ethoxy-4-(phenethylamino-methyl)-phenoxy]nicotinamide

Step 1 Synthesis of 6-(2-Ethoxy-4-formyl-phenoxy)-nicotinamide

Using a procedure similar to that of example 221 step 1, and using4-ethoxy-3-fluoro-benzaldehyde the above compound was prepared in 35%yield

¹H NMR (CD₃OD, 300 MHz) δ: 9.97 (s, 1H), 8.59 (dd, J=2.4, 0.8 Hz, 1H),8.29 (dd, J=8.6, 2.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.39 (d, J=8.3 Hz, 1H),7.09 (dd, J=8.6, 0.5 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 1.14 (t, J=7.0 Hz,3H).

Step 2

The compound of example 224 step 1 was reductively aminated withphenethylamine using procedures similarly to those previously describedto afford the title compound in 99% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.58 (dd, J=2.4, 0.5 Hz, 1H), 8.21 (dd,J=8.6, 2.4 Hz, 1H), 7.32-7.17 (m, 6H), 7.10-7.05 (m, 2H), 6.94-6.88 (m,2H), 3.94 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 2.84 (s, 4H), 1.09 (t, J=7.0Hz, 3H).

¹³C NMR (CD₃Cl, 300 MHz) δ: 166.5, 165.0, 149.7, 146.2, 140.2, 138.9,138.0, 137.6, 127.7, 127.5, 125.2, 122.8, 121.6, 119.5, 112.8, 109.4,63.3, 52.5, 49.5, 35.2, 28.7, 13.6. MS (Electrospray): (M⁺+1)392.2. MS(APCI): (M⁺+1)

EXAMPLE 225 Synthesis of6-[2-Chloro-4-(phenethylamino-methyl)-phenoxy]nicotinamide

Step 1 Synthesis of 6-(2-Chloro-4-formyl-phenoxy)-nicotinamide

7.4% yield

¹H NMR (CD₃OD, 200 MHz) δ: 9.95 (s, 1H), 8.56 (d, J=2.9 Hz, 1H),8.34-8.28 (m, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.92 (dd, J=8.4, 1.8 Hz, 1H),7.46 (d, J=8.4 Hz, 1H), 7.20-7.15 (m, 1H). MS (Electrospray): (M⁺+1)277.2

Step 2

The compound of example 225 step 1 is reductively aminated withphenethyl amine using procedures similar to those previously describedto afford the title compound in 87% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (d, J=2.4 Hz, 1H), 8.27 (dd, J=8.6, 2.4Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.34-7.18 (m, 8H), 7.05 (dd, J=8.6, 0.5Hz, 1H), 3.78 (s, 2H), 2.83 (s, 4H).

¹³C NMR (CD₃OD, 300 MHz) δ: 168.6, 165.3, 148.6, 147.6, 140.0, 139.9,139.0, 130.5, 128.7, 128.6, 128.5, 127.2, 126.3, 125.3, 124.0, 110.5,52.2, 50.4, 35.7. MS (APCI): (M⁺+1) 382.1.

EXAMPLE 226 Synthesis of6-[3-Chloro-4-(phenethylamino-methyl)-phenoxy]nicotinamide

Step 1 Synthesis of 6-(3-Chloro-4-formyl-phenoxy)-nicotinamide

7% yield

¹H NMR (CD₃OD, 200 MHz) δ: MS (APCI): (M⁺+1)

Step 2

The compound of example 226 step 1 is reductively aminated withphenethylamine using procedures similar to those previously described toafford the title compound in 51% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.62 (dd, J=2.4, 0.5 Hz, 1H), 8.27 (dd,J=8.6, 2.4 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.32-7.17 (m, 7H), 7.11-7.02(m, 2H), 3.89 (s, 2H), 2.86 (s, 4H).

¹³C NMR (CD₃OD, 300 MHz) δ: 168.1, 165.0, 153.2, 147.2, 139.4, 139.3,133.9, 133.3, 131.1, 128.2, 128.1, 125.9, 125.1, 122.1, 119.8, 110.8,49.8, 49.5, 35.1. MS (APCI): (M⁺+1)382.1.

EXAMPLE 227 Synthesis of6-[2-Methyl-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide

Using the aldehyde of Example 222 step 1, and using 3-methylbutylaminein place of phenethylamine affords the title compound.

99% yield

¹H NMR (CD₃OD, 200 MHz) δ: 8.58 (dd, J=2.6, 0.7 Hz, 1H); 8.22 (dd,J=8.4, 2.2 Hz, 1H); 7.28 (s, 1H); 7.22 (dd, J=8.0, 1.8 Hz, 1H);7.01-6.90 (m, 2H); 3.73 (s, 2H); 2.63 (d, J=7.7 Hz, 1H); 2.59 (d, J=9.1Hz, 1H); 2.11 (s, 3H); 1.67-1.51 (m, 1H); 1.48-1.36 (m, 2H); 0.89 (d,J=6.6 Hz, 6H).

¹³C NMR (CDCl₃, 300 MHz) δ: 166.2, 164.9, 149.4, 146.4, 138.3, 137.0,130.2, 129.5, 125.9, 122.8, 120.7, 109.4, 52.7, 46.9, 38.2, 25.1, 21.7,15.3. MS (APCI): (M⁺+1)328.1.

EXAMPLE 228 Synthesis of6-[2-Fluoro-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide

Using the compound of Example 223, step 1, and using 3-methylbutylamine,the title compound was prepared by reductive amination as describedpreviously.

99% yield

¹H NMR (CD₃OD, 200 MHz) δ: 8.58 (dd, J=2.7, 0.8 Hz, 1H), 8.28 (dd,J=8.6, 2.4 Hz, 1H), 7.30-7.21 (m, 3H), 7.09 (dd, J=8.9, 0.8 Hz, 1H),3.77 (s, 2H), 2.65-2.57 (m, 2H), 1.70-1.53 (m, 1H), 1.49-1.38 (m, 2H),0.91 (d, J=6.4 Hz, 7H).

¹³C NMR (CD₃OD, 200 MHz) δ: 168.7, 165.3, 154.9 (d, ¹J_(CF)=246.2),147.7, 139.8, 139.6, 139.4 (d, ³J_(CF)=6.2), 125.4, 124.9 (d,³J_(CF)=3.4), 123.9, 116.7 (d, ²J_(CF)=18.9), 110.3, 52.7, 38.6, 26.5,22.1. MS (APCI) (M⁺+1) 332.1

EXAMPLE 229 Synthesis of6-[2-Chloro-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide

Using the compound of Example 225, step 1, and using 3-methylbutylamine,affords the title compound.

73% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (dd, J=2.4, 0.8 Hz, 1H), 8.28 (dd,J=8.6, 2.4 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.3, 1.9 Hz,1H), 7.22 (d, J=8.1 Hz, 1H), 7.06 (dd, J=8.9, 0.8 Hz, 1H), 3.78 (s, 2H),2.62 (t, J=7.8 Hz, 2H), 1.63 (hep, J=6.7 Hz, 1H), 1.49-1.38 (m, 2H),0.91 (d, J=6.4 Hz, 6H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.2, 163.9, 147.2, 146.3, 138.4, 137.6,129.1, 127.1, 123.9, 122.6, 109.1. MS (APCI): (M⁺+1) 348.1

EXAMPLE 230 Synthesis of6-[2-Ethoxy-4-(3-methyl-butylamino-methyl)-phenoxy]nicotinamide

Using the compound of example 224, step 1, and using3-methoxybutylamine, the title compound is prepared by reductiveamination as described previously.

76% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.55 (d, J=1.9 Hz, 1H), 8.12 (dd, J=8.3, 2.1Hz, 1H), 7.10-6.90 (m, 4H), 6.25 (s, 2H), 3.96 (q, J=7.0 Hz, 2H), 3.77(s, 2H), 2.69-2.62 (m, 2H), 1.70-1.53 (m, 1H), 1.45-1.35 (m, 2H), 1.11(t, J=7.0 Hz, 3H), 0.88 (d, J=6.7 Hz, 6H).

¹³C NMR (CD₃OD, 300 MHz) δ: 166.4, 165.0, 149.7, 146.1, 140.1, 138.1,138.0, 122.8, 121.5, 119.5, 112.9, 109.4, 63.3, 53.0, 46.8, 38.2, 25.2,21.7, 13.6. MS (Electrospray): (M⁺+1) 358.1

EXAMPLE 231 Synthesis of6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-methyl-pbenoxy}-nicotinamide

Using the compound of Example 220, step 1 and 2-cyclopentytethylamine,the title compound is prepared by reductive amination.

78% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.60 (dd, J=2.4, 0.5 Hz, 1H), 8.24 (dd,J=8.6, 2.4 Hz, 1H), 7.29-7.20 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 6.94 (dd,J=8.9, 0.8 Hz, 1H), 3.74 (s, 2H), 2.65-2.57 (m, 2H), 2.12 (s, 3H),1.85-1.68 (m, 4H), 1.66-1.50 (m, 7H).

¹³C NMR (CD₃OD, 300 MHz) δ: 170.1, 167.4, 152.6, 149.3, 141.3, 138.5,133.2, 132.2, 129.0, 126.2, 123.3, 111.6, 54.3, 39.8, 37.2, 34.2, 26.5,16.8. MS (APCI): (M⁺+1) 354.5

EXAMPLE 232 Synthesis of6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-fluoro-phenoxy}-nicotinamide

Reductive amination of 2-cyclopentylethylamine and the compound ofExample 223, step 1, affords the title compound.

84% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (dd, J=2.4, 0.8 Hz, 1H), 8.27 (dd,J=8.6, 2.4 Hz. 1H), 7.30-7.17 (m, 3H), 7.08 (dd, J=8.6, 0.5 Hz, 1H),3.77 (s, 2H), 2.65-2.57 (m, 2H), 1.90-1.71 (m, 4H), 1.63-1.52 (m, 8H).

¹³C NMR (CD₃OD, 300 MHz) δ: 168.6, 165.3, 154.9 (d, ¹J_(CF)246.5),147.6, 139.8, 139.7 (d, ²J_(CF)=13.0), 139.3 (d, ³J_(CF)=6.0), 125.4,124.9 (d, ³J_(CF)=3.4), 123.9, 116.7 (d, ²J_(CF)=18.6), 110.3, 52.6,38.4, 35.9, 32.7, 25.1. MS (APCI): (M⁺+1) 358.2

EXAMPLE 233 Synthesis of6-{2-Chloro-4-[2-Cyclopentyl-ethylamino)-methyl]-phenoxy}-nicotinamide

Title compound is prepared by reductive amination of 2-cyclopentylamineand the compound of Example 225, step 1.

67% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (dd, J=2.7, 0.8 Hz, 1H), 8.27 (dd,J=8.6, 2.4 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.39-7.19 (m, 2H), 7.05 (dd,J=8.6, 0.8 Hz, 1H), 3.76 (s, 2H), 2.69-2.57 (m, 2H), 1.80-1.74 (m, 5H),1.61-1.54 (m, 8H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.2, 164.0, 147.2, 146.3, 138.4, 137.7,129.1, 127.1, 125.8, 123.9, 122.6, 109.1, 51.0, 37.0, 34.5, 31.3, 31.3,23.7.

EXAMPLE 234 Synthesis of6-{4-[2-Cyclopentyl-ethylamino)-methyl]-2-ethoxy-phenoxy}-nicotinamide

Reductive amination of 2-cyclopentylamine and the compound of Example224, step 1 affords the title compound 91% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.57 (dd, J=2.7, 0.8 Hz, 1H), 8.23 (dd,J=8.6, 2.4 Hz, 1H), 7.14-7.10 (m, 2H), 7.01 (d, J=1.9 Hz, 1H), 6.94 (dd,J=8.6, 0.3 Hz, 1H), 3.99 (q, J=7.3 Hz, 2H), 3.83 (s, 2H), 2.73-2.65 (m,2H), 1.81-1.76 (m, 4H), 1.65-1.54 (m, 7H), 1.11 (t, J=7.0 Hz, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.3, 164.9, 149.8, 146.2, 140.4, 138.1,136.6, 123.3, 121.2, 119.8, 113.1, 108.7, 63.0, 51.8, 37.0, 34.3, 31.3,23.7, 12.6. MS (APCI): (M⁺+1) 384.2.

EXAMPLE 235 Synthesis of6-{2-Methyl-4-[2-thiophen-2-yl-ethylamino)-methyl]-phenoxy}-nicotinamide

Reductive amination of 2-thiophen-2-yl-ethylamine and the compound ofExample 222, step 1 affords the title compound following the procedureof example 222, step 2.

30% yield.

¹H NMR (CD₃OD, 300 MHz) δ: 8.62 (d, J=2.2 Hz, 1H), 8.26 (dd, J=8.7, 2.4Hz, 1H), 7.28-7.21 (m, 3H), 7.03-6.87 (m, 4H), 3.78 (s, 2H), 3.10-3.05(m, 2H), 2.90 (t, J=7.1 Hz, 3H), 2.13 (s, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 168.2, 165.5, 150.7, 147.4, 141.7, 139.4,136.7, 131.2, 130.2, 127.1, 126.4, 126.2, 124.7, 124.3, 123.1, 121.4,109.6, 52.1, 50.0, 29.2, 14.9. MS (APCI): (M⁺+1) 368.1.

EXAMPLE 236 Synthesis of6-(4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-nicotinamide

The compound of example 222, step 1 is reductively aminated with2-(3-fluoro-phenyl)-ethylamine following the procedure of example 222,step 2 to afford the title compound.

55% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.60 (d, J=2.4 Hz, 1H), 8.24 (dd, J=8.6, 2.4Hz, 1H), 7.33-7.18 (m, 3H), 7.04-6.87 (m, 5H), 3.76 (s, 2H), 2.84 (s,4H), 2.10 (s, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.3, 164.6, 162.0 (d, ¹J_(CF)=242.7),149.8, 146.5, 141.6 (d, ³J_(C-F)=7.4), 138.5, 135.7, 130.3, 129.4, 128.8(d, ³J_(CF)=8.3), 126.2, 123.4, 123.2 (d, ⁴J_(CF)=2.8), 120.5, 114.0 (d,²J_(CF)=20.8), 111.5 (d, ²J_(CF)=21.1), 108.8, 51.3, 48.6, 34.0 (d,⁴J_(CF)=1.4), 14.0. MS (APCI): (M⁺+1) 380.2.

EXAMPLE 237 Synthesis of6-{2-Methyl-4-[(2-o-tolyl-ethylamino)-methyl]-phenoxy}-nicotinamide

The titled compound results from the reductive amination reaction of thecompound of example 222, step 1 and 2-o-tolyl-ethylamine following theprocedure of example 222, step 2.

78% yield.

¹H NMR (CD₃OD, 300 MHz) δ: 8.62 (dd, J=1.6, 0.6 Hz, 1H), 8.25 (dd,J=8.9, 2.6 Hz, 1H), 7.27-7.09 (m, 6H), 7.01 (d, J=8.3 Hz, 1H), 6.94 (dd,J=8.7, 1.0 Hz, 1H), 3.78 (s, 2H), 2.88-2.77 (m, 4H), 2.30 (s, 3H), 2.12(s, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.3, 164.6, 149.8, 146.5, 138.5, 136.6,135.7, 134.8, 130.3, 129.4, 128.9, 127.9, 126.1, 125.0, 124.7, 123.4,120.5, 108.7, 51.3, 31.7, 17.0, 14.0. MS (APCI): (M⁺+1) 376.1

EXAMPLE 238 Synthesis of6-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-methyl-phenoxy}-nicotinamide

The reaction of the compound of Example 222, step 1 and3,3-dimethyl-butylamine following the procedure of example 222, step 2affords the title compound.

61% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.60 (dd, J=2.4, 0.5 Hz, 1H), 8.24 (dd,J=8.9, 2.7 Hz, 1H), 7.29-7.21 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 6.93 (dd,J=8.9, 0.8 Hz, 1H), 3.74 (s, 2H), 2.67-2.59 (m, 2H), 2.12 (s, 3H),1.51-1.43 (m, 2H), 0.92 (s, 9H).

¹³C NMR (CD₃OD, 300 MHz) δ: 168.2, 165.5, 150.7, 147.5, 139.4, 136.7,131.3, 130.3, 127.1, 124.32, 121.4, 109.6, 52.6, 44.7, 42.7, 29.1, 28.5,14.9.

EXAMPLE 239 Synthesis of6-(4-{[2-(3-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-nicotinamide

The reaction of the compound of Example 222, step 1 and3-chloro-phenethylamine affords the title compound following theprocedure of example 222, step 2.

55% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.60 (dd, J=2.7, 0.8 Hz, 1H), 8.24 (dd,J=8.6, 2.4 Hz. 1H), 7.31-7.11 (m, 7H), 7.00 (d, J=8.3 Hz, 1H), 6.94 (dd,J=8.9, 0.8 Hz, 1H), 3.76 (s, 2H), 2.83 (s, 4H), 2.12 (s, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.3, 164.6, 149.8, 146.5, 141.2, 138.5,135.8, 132.9, 130.3, 129,4, 128.6, 127.4, 126.2, 125.8, 125.0, 123.4,120.5, 108.7, 51.3, 48.6, 34.0, 14.0. MS (APCI): (M⁺+1) 396.1

EXAMPLE 240 Synthesis of6-(4-Butylaminomethyl-2-methyl-phenoxy)-nicotinamide

The reductive amination of the compound of Example 222, step 1 andbutylamine following the procedure of example 222, step 2, affords thetitle compound

56% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.61 (dd, J=2.7, 0.8 Hz, 1H), 8.25 (dd,J=8.9, 2.7 Hz, 1H), 7.29-7.20 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.93 (dd,J=8.9, 0.8 Hz, 1H), 3.73 (s, 2H), 2.63-2.55 (m, 2H), 2.12 (s, 3H),1.65-1.46 (m, 2H), 1.41-1.24 (m, 2 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.3, 164.6, 149.8, 1446.5, 138.4, 135.9,130.3, 129.3, 126.2, 123.4, 120.4, 108.7, 51.5, 30.2, 19.2, 14.0, 12.0.MS (APCI): (M⁺+1) 314.2

EXAMPLE 241 Synthesis of6-(2-Methyl-4-{[methyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinamide

A solution of Example 227 (1.0 equiv) in MeOH (0.2 M solution) wastreated with formaldehyde (5 equiv) and stirred at room temperature(r.t.) for 2 hours. Sodium Borohydride was added and stirred at r.t.overnight. The solvent was removed under vacuum and crude residue waspurified by silica gel chromatography using the appropriate eluent(typically mixtures CHCl₃/EtOH 7%/NH4OH 0.7%) to afford the titlecompound as a solid.

20% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.61 (dd, J=2.7, 0.8 Hz, 1H), 8.25 (dd,J=8.6, 2.4 Hz, 1H), 7.28-7.19 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 6.95 (dd,J=8.6, 0.8 Hz, 1H), 3.53 (s, 2H), 2.48-2.41 (m, 2H), 2.23 (s, 3H), 2.13(s, 3H), 1.66-1.53 (m, 1H), 1.51-1.40 (m, 2H), 0.91 (d, J=6.2 Hz, 6H).

¹³C NMR (CD₃OD, 200 MHz) δ: 167.3, 164.6, 150.0, 146.5, 138.5, 134.2,131.4, 129.2, 127.3, 123.4, 120.3, 108.8, 60.1, 54.3, 39.95, 34.5, 25.4,20.7, 13.9. MS (APCI): (M⁺+1) 342.2

EXAMPLE 242 Synthesis of6-{2-Methyl-4-[(methyl-phenethyl-amino)-methyl]-phenoxy}-nicotinamide

N-methyl-phenethylamine when reacted with the compound of Example 220,step 1 following the procedure of example 222, step 2 affords the titlecompound.

47% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.62-8.59 (m, 1H), 8.25 (dd, J=8.9, 2.7 Hz,1H), 7.29-7.10 (m, 7H), 6.95 (dd, J=11.0, 8.3 Hz, 1H), 6.92 (d, J=8.6Hz, 1H), 3.56 (s, 2H), 2.87-2.77 (m, 2H), 2.71-2.60 (m, 2H), 2.30 (s,3H), 2.10 (s, 3H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.2, 164.6, 150.0, 146.5, 139.0, 138.5,134.2, 131.3, 129.2, 127.4, 127.2, 127.0, 124.7, 123.4, 123.1, 120.3,108.8, 59.8, 57.6, 39.9, 31.8, 14.0. MS (APCI): (M⁺+1) 376.2

EXAMPLE 243 Synthesis of3-Fluoro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide

Step 1 Synthesis of 3-Fluoro-4-(4-formyl-phenoxy)-benzonitrile

Basic displacement reaction of 4-hydroxy benzaldehyde and 3,4difluorobenzonitrile using potassium carbonate in anhydrous DMF atreflux temperatures affords the above compound.

32% Yield

¹H NMR (CDCl₃, 200 MHz) δ: 9.92 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.76(dd, J=10.2, 1.8 Hz, 1H), 7.64-7.58 (m, 1H), 7.34 (d, J=8.4 Hz, 1H),7.18 (d, J=8.8 Hz, 2H). MS (APCI): (M⁺−1) 240.0.

Step 2 Synthesis of 3-Fluoro-4-(4-formyl-phenoxy)-benzamide

Hydrolysis of the compound of step 1 using hydrogen peroxide andpotassium carbonate in DMSO as described previously afford the abovecompound in 99% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 9.89 (s, 1H), 7.94-7.89 (m, 2H), 7.84-7.74(m, 2H), 7.32-7.23 (m, 1H), 7.12 (d, J=8.8 Hz, 2H). MS (APCI): (M⁺+1)260.1

Step 3

The reaction of phenethylamine and the compound of Example 243, step 2under reductive amination conditions affords the title compound.

47% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 11.68 (dd, J=11.5, 2.0 Hz, 1H), 11.52 (ddd,J=8.5, 1.8, 1.0 Hz, 1H), 11.03-10.74 (m, 7H), 10.61-10.47 (m, 3H), 5.65(s, 2H), 4.25 (s, 4H).

¹³C NMR (CD₃OD, 300 MHz) δ: 167.8, 154.4, 152.2 (d, ¹J_(CF)=247.0),146.4 (d, ²J_(CF)=11.4), 138.6, 134.1, 128.9, 128.8, 127.3, 127.2,124.9, 123.2 (d, ³J_(CF)=3.7), 118.8, 116.9, 115.2 (d, ²J_(CF)=19.7),51.2, 49.0, 34.2.

EXAMPLE 244 Synthesis of3-Chloro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide

Step 1 Synthesis of 3-Chloro-4-(4-formyl-phenoxy)-benzonitrile

The above compound is prepared by nucleophilic displacement reaction of4-hydroxy benzaldehyde and 3-chloro-4-fluorobenzonitrile under basicconditions as described in Example 243, step 1.91% yield.

¹H NMR (CDCl₃, 200 MHz) δ: 9.96 (s, 1H), 7.91 (dd, J=6.9, 2.2 Hz, 2H),7.79 (d, J=1.8 Hz, 1H), 7.56 (dd, J=8.4, 2.2 Hz, 1H), 7.11-7.07 (m, 2H).MS (Electrospray): (M⁺+1)258.0

Step 2 Synthesis of 3-Chloro-4-(4-formyl-phenoxy)-benzamide

99% Yield.

¹H NMR (CD₃OD, 200 MHz) δ: 9.96 (s, 1H), 8.00 (d, J=2.1 Hz, 1H), 7.89(d, J=8.9 Hz, 2H), 7.73 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.06 (d, J=8.6Hz, 2H). MS (APCI): (M⁺+1)276.0

Step 3

The reductive amination reaction of the compound of Example 242, step 2(as described above) with phenethylamine affords the title compound.

48% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 8.04 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.6, 2.4Hz, 1H), 7.38-7.18 (m, 7H), 7.00-6.93 (m, 3H), 3.80 (s, 2H), 2.85 (s,4H).

¹³C NMR (CD₃OD, 200 MHz) δ: 170.5, 157.5, 157.0, 141.2, 136.7, 132.0,131.9, 131.5, 130.1, 130.0, 129.3, 127.8, 126.4, 120.4, 53.9, 51.7,36.8. MS (APCI): (M⁺+1)381.2

EXAMPLE 245 Synthesis of2-Chloro-4-[4-(phenethylamino-methyl)-phenoxy]-benzamide

Step 1 Synthesis of 2-Chloro-4-(4-formyl-phenoxy)-benzonitrile

4-Hydroxy benzaldehyde (1 equiv), 2-chloro-4-fluorobenzonitrile (1equiv) and K₂CO₃ (2.5 equiv) in anhydrous DMF (0.2 M) were heated at110° C. under nitrogen during 1 hour (the reaction can be monitored bytlc). After cooling down to room temperature, the reaction mixture waspoured into water and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedunder vacuum (toluene was added to aid DMF evaporation). The crudemixture was purified by flash chromatography using hexanes/ethyl acetate(4:1) as eluent.

84% yield.

¹H NMR (CDCl₃, 200 MHz) δ: 9.99 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.65(d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.15-7.13 (m, 2H), 6.99 (dd, J=8.4, 2.2Hz, 1H). MS (Electrospray): (M⁺+1)258.1.

Step 2 Synthesis of 2-Chloro-4-(4-formyl-phenoxy)-benzamide

A solution of 2-chloro-4-(4-formylphenoxy)benzonitrile (1.0 equiv) inDMSO (0.2 M solution) was treated with K₂CO₃ (0.5 equiv) and 33% H₂O₂.After 12 h, the reaction mixture was poured into H₂O and extracted withethyl acetate. The combined organic layers were washed twice with waterand brine. After drying the extracts over magnesium sulfate andevaporation under vacuum, the crude product was purified by silica gelchromatography using the aprropriate eluent (typically mixtures ofhexanes/ethyl acetate) to afford the title compound as a solid.

99% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 9.92 (s, 1H), 7.97-7.92 (m, 2H), 7.57 (d,J=8.4 Hz, 1H), 7.19-7.15 (m, 3H), 7.07 (dd, J=8.4, 2.2 Hz, 1H). MS(Electrospray): (M⁺+1)276.0.

Step 3

Reacting phenethylamine with the compound of Example 245, step 2 underreductive amination conditions (described previously) affords the titlecompound.

34% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 6.12 (d, J=8.6 Hz, 1H), 5.99 (d, J=8.6 Hz,2H), 5.88-5.79 (m, 5H), 5.66-5.51 (m, 4H), 2.42 (s, 2H), 1.46 (s, 4H).

¹³C NMR (CD₃OD, 300 MHz) δ: 170.6, 159.8, 155.1, 139.5, 135.3, 132.1,130.5, 130.3, 128.5, 128.4, 126.2, 119.8, 118.9, 116.1, 52.2, 50.1,35.2. MS (APCI): (M⁺+1) 380.9.

EXAMPLE 246 Synthesis of3-Fluoro-4-{2-methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Step 1 Synthesis of 3-Fluoro-4-(4-formyl-2-methyl-phenoxy)-benzonitrile

38% yield.

¹H NMR (CDCl₃, 300 MHz) δ: 9.95 (s, 1H), 7.83 (s, 1H), 7.71 (dd, J=8.3,1.6 Hz, 1H), 7.53 (dd, J=9.9, 1.9 Hz, 1H), 7.47-7.43 (m, 1H), 7.02 (t,J=8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 2.37 (s, 3H).

¹³C NMR (CDCl₃, 300 MHz) δ: 189.9, 157.4, 152.0 (d, ¹J_(CF)=252.1),146.9 (d, ²J_(CF)=11.0), 132.2, 13.0, 129.0, 128.7, 128.6, 120.3, 120.0,119.9 (d, ³J_(CF)=1.4), 116.7, 116.3 (d, ³J_(CF)=2.3), 107.1 (d,²J_(CF)=8.1), 15.0.

Step 2 Synthesis of 3-Fluoro-4-(4-formyl-2-methyl-phenoxy)-benzamide

88% yield.

¹H NMR (CD₃OD, 200 MHz) δ: 9.87 (s, 1H), 7.84-7.82 (m, 2H), 7.77-7.68(m, 2H), 7.14 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.37 (s, 3H).MS (Electrospray): (M⁺+1) 274.0

Step 3

The reaction of 3-methylbutylamine and the compound of Example 246, step2 under reductive amination conditions affords the title compound.

68% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 7.76 (dd, J=11.6, 1.6 Hz, 1H), 7.61 (d, J=8.1Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.89-6.75 (m, 2H), 3.71(s, 2H), 2.64-2.56 (m, 2H), 2.21 (s, 3H), 1.68-1.51 (m, 1H), 1.48-1.37(m, 2H), 0.90 (d, J=6.5 Hz, 6H).

¹³C NMR (CD₃OD, 200 MHz) δ: 167.2, 150.8 (d, ¹J_(CF)=245.8), 150.9,146.6 (d, ²J_(CF)=11), 134.5, 130.0, 127.6, 127.2 (d, ³J_(CF)=5.5),125.7, 122.5 (d, ³J_(CF)=3.1), 117.2, 116.0, 114.4 (d, ²J_(CF)=19.6),50.9, 45.2, 36.4, 24.5, 20.0, 13.0. MS (Electrospray): (M⁺+1) 345.4.

EXAMPLE 247 4-(4-Benzylaminomethylphenoxy)-benzamide

Step 1 4-(4-Formyl-phenoxy)-benzonitrile

Combine 4-fluorobenzonitrile (3.96 g, 32.7 mmol), 4-hydroxybenzaldehyde(3.99 g, 32.7 mmol), dimethyl acetamide (100 mL), and potassiumcarbonate (6.8 g, 49 mmol), stir, and heat to 130° C. After 18 h, coolto ambient temperature, partially remove the solvent in vacuo, anddilute with 100 mL of water. Extract the aqueous solution with diethylether (3×150 mL), wash the organic phase with water (2×100 mL), andbrine (100 mL). Dry the organic phase over magnesium sulfate, filter,and concentrate under vacuum. Purify via a Biotage Flash 40L system,using a gradient: 5:95 hexanes/ethyl acetate to 50:50 hexanes/ethylacetate to give the title compound (3.6 g, 49%) as a white solid: ¹H NMR(chloroform-d): 9.95 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 7.14 (m, 4H).

Step 2 4-(4-Formyl-phenoxy)-benzamide

Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol),dimethylsufoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature.Dilute with 100 mL of water, extract with ethyl acetate (3×100 mL). Washthe organic phase with 100 mL of water, and 50 mL of brine. Dry theorganic phase over sodium sulfate, filter, and concentrate under vacuum.Purify via aBiotage Flash 40L system using 75:25 hexanes/ethyl acetateas eluting solvent to give 3.0 g (77%) of the title compound: ¹H NMR(chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (brm, 2H).

Step 3

Combine 4-(4-Formyl-phenoxy)-benzamide from Example 247, step 2 (0.1 g,0.41 mmol), benzylamine (0.040 g, 0.38 mmol), 4 {acute over (Å)}molecular sieves (1 g) in methanol (5 mL) and stir for 18 h at ambienttemperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 66 hat ambient temperature. Filter through a 5 g SCX column, eluting firstwith 1:1 dichloromethane/methanol. Discard the first washings, thenelute with 1:1 dichloromethane/2 M ammonia in methanol. Collect theeluants and concentrate in vacuo. Purify by Chromatotron, on a 2 mmsilica plate, eluting with 90:10:1 dichloromethane/ethanol/ammoniumhydroxide to afford the title compound (0.058 g, 46%): mass spectrum(ion spray): m/z=333.06 (M+1); ¹H NMR (DMSO-d₆): 7.82 (m, 3H), 7.39-7.18(m, 8H), 7.02-6.97 (m, 4H), 3.67-3.66 (2s, 4H).

EXAMPLE 248 4-(4-Phenethylaminomethylphenoxy)-benzamide

Combine 4-(4-Formyl-phenoxy)-benzamide (from Example 247, step 2)(0.39g, 1.6 mmol), phenethylamine (0.15 g, 1.2 mmol), 20 mL of methanol and 2g of 3 {acute over (Å)} molecular sieves, and stir at ambienttemperature under nitrogen for 5 h. Add sodium borohydride (0.18 g, 4.8mmol), and stir at ambient temperature for 18 h at ambient temperature.Filter the reaction mixture through Celite, and adsorb on silica gel.Purify by Biotage Flash 40S, eluting with 95:5:0.5chloroform/ethanol/ammonium hydroxide to afford 0.27 g (93%) of thetitle compound: mass spectrum (ion spray): m/z=347.28 (M+1); HPLCretention time: 6.01 min (HPLC method in this experiment and subsequentexperiments: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at254 nM).

EXAMPLE 249 6-[4-(Benzylamino-methyl)-phenoxy]-nicotinamide

Step 1 6-(4-Formyl-phenoxy)-nicotinamide

Combine 6-chloronicotinamide (4.53 g, 28.9 mmol), 4-hydroxybenzaldehyde(3.5 g, 28.9 mmol), potassium carbonate (6 g, 43.4 mmol), anddimethylformamide (200 mL). Heat the reaction mixture to 130° C. undernitrogen, and stir for 18 h. Dilute the reaction mixture with 200 mL ofwater, extract with diethyl ether (4×100 mL) and dichloroethane (2×100mL). Combine the organics, and dry over magnesium sulfate. Filter, andconcentrate in vacuo. Adsorb the residue on silica, and purify byBiotage Flash 40L (elute with 50:50 hexanes/ethyl acetate to 100% ethylacetate) to afford the title compound as a white solid (3.2 g, 46%): ¹HNMR (DMSO-d₆): 10.0 (s, 1H), 8.59 (d, 1H), 8.26-8.22 (dd, 1H), 7.98-7.95(m, 2H), 7.10-7.07 (d, 1H), 6.15-5.65 (br m, 2H).

Step 2

Combine 6-(4-Formyl-phenoxy)-nicotinamide (0.097 g, 0.4 mmol) in 5 mL ofmethanol with benzylamine (0.4 mmol), and 1 g of 3 {acute over (Å)}molecular sieves. Stir for 18 h. Add sodium borohydride (0.076 g, 2mmol), and stir for 18 h. Flush the reactions down through a 5 g SCXcolumn, first wash with 1:1 chloroform/methanol, then collect washeswith 1:1 chloroform/2 M ammonia in methanol. Adsorb the collectedmaterial on silica, then purify via a ISCO® Combiflash 16× system (use a10 g silica cartridge, and elute with 98:2:0.2chloroform/ethanol/ammonium hydroxide, gradient to 90:10:1chloroform/ethanol/ammonium hydroxide). ¹H NMR (DMSO-d₆): 8.58 (d, 1H),8.22 (m, 1H), 8.0 (s, 1H), 7.46 (s, 1H), 7.27-7.38 (m, 6H), 7.20 (m, 1H)7.02-7.08 (m, 3H), 3.67-3.68 (d, 4H). TLC R_(f) (90:10:1chloroform/ethanol/ammonium hydroxide): 0.31.

The following examples were synthesized in a manner similar to Example249:

mass HPLC Ex- spec r.t., % ample Name (M+) min purity 2506-(4-Allylaminomethyl-phenoxy)- 284 3.87 99 nicotinamide 2516-{4-[(4-Methoxy-benzylamino)- 364 0.79 99 methyl]-phenoxy}-nicotinamide252 6-{4-[(3-Trifluoromethyl-benzylamino)- 364 0.87 99methyl]-phenoxy}-nicotinamide 253 6-{4-[(2-Thiophen-2-yl-ethylamino)-353 0.78 99 methyl]-phenoxy}-nicotinamide 2546-{4-[(3-Fluoro-benzylamino)-methyl]- 351 0.78 99 phenoxy}-nicotinamide255 6-(4-{[(Furan-2-ylmethyl)-amino]- 324 0.74 100methyl}-phenoxy)-nicotinamide 256 6-(4-{[2-(3-Fluoro-phenyl)- 366 0.83100 ethylamino]-methyl}-phenoxy)- nicotinamide 2576-{4-[(4-Trifluoromethoxy- 418 0.89 99.6 benzylamino)-methyl]-phenoxy}-nicotinamide 258 6-[4-(Phenethylamino-methyl)- 348 5.87 91.2phenoxy]-nicotinamide 259 6-(4-{[2-(3-Chloro-phenyl)- 382 6 98.9ethylamino]-methyl}-phenoxy)- nicotinamide 2606-(4-{[2-(4-Sulfamoyl-phenyl)- 427 5.65 89 ethylamino]-methyl}-phenoxy)-nicotinamide 261 6-{4-[(3-Phenyl-propylamino)-methyl]- 362 5.94 99phenoxy}-nicotinamide 262 6-{4-[(3,3-Diphenyl-propylamino)- 438 6.2398.7 methyl]-phenoxy}-nicotinamide 263 6-{4-[(3,3-Dimethyl-butylamino)-328 5.87 97.2 methyl]-phenoxy}-nicotinamide 2646-(4-{[2-(2-Methoxy-phenyl)- 378 5.91 98.9 ethylamino]-methyl}-phenoxy)-nicotinamide 265 6-{4-[(2-Phenylamino-ethylamino)- 363 5.87 99.2methyl]-phenoxy}-nicotinamide 266 6-{4-[(2-Phenyl-propylamino)-methyl]-362 5.94 98.4 phenoxy}-nicotinamide 2676-{4-[(2-Pyridin-2-yl-ethylamino)- 349 5.49 98.5methyl]-phenoxy}-nicotinamide 268 6-(4-{[2-(2-Chloro-phenyl)- 382 5.9698.7 ethylamino]-methyl}-phenoxy)- nicotinamide 2696-{4-[(2-Pyridin-3-yl-ethylamino)- 349 5.47 90.9methyl]-phenoxy}-nicotinamide 270 6-{4-[(2,2-Diphenyl-ethylamino)- 4246.16 99 methyl]-phenoxy}-nicotinamide 2716-{4-[(3-Methyl-butylamino)-methyl]- 314 5.79 99 phenoxy}-nicotinamide272 6-{4-[(2-Cyclohexyl-ethylamino)- 354 6.05 96methyl]-phenoxy}-nicotinamide 273 6-{4-[(2-Methylsulfanyl-ethylamino)-317 5.56 99.6 methyl]-phenoxy}-nicotinamide 2746-{4-[(6-Hydroxy-hexylamino)- 344 5.51 99.9methyl]-phenoxy}-nicotinamide 275 6-{4-[(2-Dimethylamino-ethylamino)-315 5.4 99.9 methyl]-phenoxy}-nicotinamide 2766-(4-Decylaminomethyl-phenoxy)- 384 6.37 98.7 nicotinamide 2776-{4-[(2-Ethyl-hexylamino)-methyl]- 356 6.07 99.7 phenoxy}-nicotinamide278 6-(4-{[(Tetrahydro-furan-2-ylmethyl)- 328 5.54 99.9amino]-methyl}-phenoxy)-nicotinamide 2796-{4-[(2-Pyrrolidin-1-yl-ethylamino)- 341 5.41 99.9methyl]-phenoxy}-nicotinamide 280 6-(4-{[2-(1-Methyl-pyrrolidin-2-yl)-356 5.42 99.8 ethylamino]-methyl}-phenoxy)- nicotinamide 2816-(4-{[2-(1H-Imidazol-4-yl)- 338 5.4 99.7 ethylamino]-methyl}-phenoxy)-nicotinamide 282 6-(4-{[3-(2-Methyl-piperidin-1-yl)- 383 5.46 99.9propylamino]-methyl}-phenoxy)- nicotinamide 2836-{4-[(2-Diisopropylamino- 371 5.46 99.9 ethylamino)-methyl]-phenoxy}-nicotinamide 284 6-{4-[(2-Cyclohex-1-enyl-ethylamino)- 352 5.93 99.6methyl]-phenoxy}-nicotinamide 285 6-(4-Pentylaminomethyl-phenoxy)- 3135.94 98 nicotinamide

The following examples were synthesized in a manner similar to Example248:

mass HPLC % Example Name spec (M+) r.t., min purity 2864-{4-[(4-Trifluoromethoxy-benzylamino)- 417 1.02 94methyl]-phenoxy}-benzamide 287 4-(4-{[2-(3-Chloro-phenyl)-ethylamino]-381 0.95 96.7 methyl}-phenoxy)-benzamide 2884-{4-[(4-Trifluoromethyl-benzylamino)- 401 0.98 93.4methyl]-phenoxy}-benzamide 289 4-{4-[(4-Fluoro-benzylamino)-methyl]- 3510.84 90 phenoxy}-benzamide 290 4-(4-Pentylaminomethyl-phenoxy)-benzamide351 0.84 95.5 291 4-{4-[(2-Phenyl-propylamino)-methyl]- 361 6.11 97.6phenoxy}-benzamide 292 4-(4-{[2-(2-Chloro-phenyl)-ethylamino]- 381 6.0999.1 methyl}-phenoxy)-benzamide 2934-(4-{[2-(2,4-Dichloro-phenyl)-ethylamino]- 415 6.2 99.9methyl}-phenoxy)-benzamide 294 4-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-365 6.02 99.8 methyl}-phenoxy)-benzamide 2954-(4-{[2-(3-Fluoro-phenyl)-ethylamino]- 365 6.02 99.9methyl}-phenoxy)-benzamide 296 4-(4-{[2-(2-Fluoro-phenyl)-ethylamino]-365 6.05 99.7 methyl}-phenoxy)-benzamide 2974-(4-{[2-(2,5-Dimethoxy-phenyl)-ethylamino]- 407 6.07 99.3methyl}-phenoxy)-benzamide 2984-(4-{[2-(2,6-Dichloro-phenyl)-ethylamino]- 415 6.2 99.8methyl}-phenoxy)-benzamide 299 4-{4-[(2-o-Tolyl-ethylamino)-methyl]- 3616.11 99.6 phenoxy}-benzamide 3004-{4-[(2,2-Diphenyl-ethylamino)-methyl]- 423 6.26 99.9phenoxy}-benzamide 301 4-[4-(3-Phenyl-propylamino)-phenoxy]- 347 1.54 93benzamide 302 4-{4-[(2-Cyclopentyl-ethylamino)-methyl]- 339 6.13 97phenoxy}-benzamide 303 4-{4-[(2,6-Dichloro-benzylamino)-methyl]- 4016.02 98.8 phenoxy}-benzamide

EXAMPLE 304

Combine 4-(4-Formyl-phenoxy)-benzamide (from example 247, step 2)(0.12g, 0.5 mmol) in 3 mL of methanol with Furan-2-yl-methylamine (0.024 g,0.25 mmol), and 0.5 g of 3 {acute over (Å)} molecular sieves. Stir for18 h. Add to this sodium borohydride (0.046 g, 1.25 mmol), stir for 18h. Elute down through a 5 g SCX column, first wash with 1:1chloroform/methanol (discard these washes), then with 1:1 chloroform/2 NNH₃ in MeOH, with the washings being collected. Adsorb on silica gel,purify by ISCO® 100 g (10 g silica column) and elute with 95:5:0.5chloroform/ethanol/ammonium hydroxide to afford 34 mg of product. TLCR_(f) (95:5:0.5 chloroform/ethanol/ammonium hydroxide): 0.25. ¹H NMR(DMSO-d₆): 7.86 (d, 4 H), 7.54 (s, 1 H), 7.36 (d, 2 H), 7.27 (s, 1 H),7.0 (m, 4 H), 6.37 (s, 1 H), 6.24 (s, 1 H), 3.66 (s, 2 H), 3.64 (s, 2H).

The following examples were synthesized in a manner similar to Example304

mass HPLC % Example Name spec (M+) r.t., min purity 3056-(4-{[2-(3,4-Dichloro-phenyl)- 416 6.06 99.4ethylamino]-methyl}-phenoxy)- nicotinamide 3066-(4-{[2-(2-Ethoxy-phenyl)- 392 6.04 99.3 ethylamino]-methyl}-phenoxy)-nicotinamide 307 6-{4-[(2-o-Tolyl-ethylamino)- 362 5.95 99.6methyl]-phenoxy}-nicotinamide 308 6-(4-{[2-(2-Phenoxy-phenyl)- 440 6.1994.7 ethylamino]-methyl}-phenoxy)- nicotinamide

EXAMPLE 3096-{4-[(2-Cyclopentyl-ethylamino)-methyl]-phenoxy}-nicotinamide

Combine 6-(4-formyl-phenoxy)-nicotinamide (0.61 g, 2.54 mmol) with2-Cyclopentyl-ethylamine (0.38 g, 3.3 mmol), 2 g of 3 {acute over (Å)}molecular sieves, and 10 mL of methanol. Stir for 18 h under nitrogen.Add sodium borohydride (0.5 g, 13.2 mmol), and stir for 24 h. Filterthrough Celite, remove the solvent in vacuo. Partition the residuebetween water (50 mL) and ethyl acetate (100 mL). Dry the organic phase(sodium sulfate), filter, and concentrate in vacuo. Adsorb on silica,and purify on an ISCO® 100 g system (eluting with 95:5:0.5 to 90:10:1chloroform/ethanol/ammonium hydroxide) to afford 0.45 g of product. HPLCretention time: 5.93 min (98.7% purity), ESMS (M+): 340.

General Procedures and Intermediates General Procedure for NucleophilicAromatic Substitutions

Dissolve the corresponding aldehyde (1 equiv), 6-chloronicotinonitrile(1 equiv) and K₂CO₃ (2.5 equiv) in anhydrous DMF (0.2 M) and heat atabout 110° C. under nitrogen for about 1 hour (the reaction can bemonitored by tlc). After cooling down to room temperature, the reactionmixture is poured into water and extracted with ethyl acetate (3×50 mL).The combined organic layer is dried over Na₂SO₄, filtered andconcentrated under vacuum (toluene may be added to aid DMF evaporation).The crude mixture is purified by flash chromatography usinghexanes/ethyl acetate (4:1) as eluant.

6-(2-Ethoxy-4-formyl-phenoxy)nicotinonitrile

90% yield.

¹H NMR (CHCl₃-d₃) δ: 9.95 (s, 1H, CHO), 8.37 (dd, 1H, J=2.6, 0.7 Hz),7.90 (dd, 1H, J=8.8, 2.6 Hz), 7.50-7.33 (m, 2H), 7.32 (m, 1H), 7.10 (dd,1H, J=8.8, 0.7 Hz), 4.03 (q, 2H, J=7.0 Hz), 1.14 (t, 3H, J=7.0 Hz).

¹³C NMR (CHCl₃-d₃) δ: 190.9, 164.9, 151.3, 151.7, 146.8, 142.1, 135.0,124.8, 123.1, 116.6, 112.0, 111.6, 104.3, 64.4, 14.3.

6-(2,6-Dimethyl-4-formyl-phenoxy)nicotinonitrile

88% yield.

¹H NMR (CHCl₃-d₃) δ: 9.93 (s, 1H, CHO), 8.37 (dd, 1H, J=2.4, 0.7 Hz),7.92 (dd, 1H, J=8.8, 2.4 Hz), 7.64 (s, 2H), 7.09 (dd, 1H, J=8.8, 0.7Hz), 2.14 (s, 6H).

¹³C NMR (CHCl₃-d₃) δ: 191.3, 164.2, 154.4, 152.2, 142.5, 134.0, 132.0,130.4, 116.5, 111.1, 104.3, 16.4.

6-(5-Methoxy-4-formyl-phenoxy)nicotinonitrile

12% Yield.

¹H NMR (CHCl₃-d₃) δ: 10.38 (s, 1H, CHO), 8.44 (dd, 1H, J=2.7, 0.7 Hz),7.92 (dd, 1H, J=2.7, 8.8 Hz), 7.84 (d, 1H, J=8.8 Hz), 7.05 (dd, 1H,J=8.8, 0.7 Hz), 6.78 (m, 2H), 3.89 (s, 3H).

¹³C NMR (CHCl₃-d₃) δ: 187.4, 163.7, 162.2, 157.8, 151.0, 141.6, 129.2,121.5, 115.4, 112.7, 111.5, 104.2, 104.0, 54.9.

General Procedure: Nucleophilic Aromatic Substitution6-chloronicotinamide

A solution of 4-hydroxy-3-methylbenzaldehyde (1.0 equiv) in DMF (0.2 Msolution) was treated with K₂CO₃ (1.5 equiv) and 6-chloronicotinamide(1.0 equiv). The reaction mixture was placed inside the microwave ovenand then irradiated for 5 min. Upon completion of the reaction, themixture was cooled, poured into H₂O and extracted with ethyl acetate,and the combined organic layers were washed twice with water and brine.After drying the extracts over magnesium sulfate and evaporation undervacuum the crude product was purified by silica gel chromatography usingCHCl₃: EtOH 7%: NH₄OH 0.7% to afford the title compound as a solid.

6-(4-Formyl-2,5-dimethylphenoxy)nicotinamide

38% Yield.

¹H NMR (MeOH-d₄) δ: 9.90 (s, 1H, CHO), 8.51 (dd, 1H, J=2.6, 0.7 Hz),8.25 (dd, 1H, J=8.8, 2.6 Hz), 7.68 (s, 2H), 7.10 (dd, 1H, J=8.8, 0.7Hz), 2.14 (s, 6H).

MS (Electrospray): 271.0 (M⁺+1).

General Procedure: Reductive Amination

A mixture of aldehyde (1 equiv), amine (1 equiv), 4 {acute over (Å)}molecular sieves (1000% weight) in methanol (0.1 M) was stirredovernight under nitrogen atmosphere at room temperature. The followingday NaBH₄ (5 equiv) was added and the reaction mixture was stirred for 3hours. The reaction can be monitored by electrospray MS. The reactionmixture was filtered off and the solvent evaporated to yield a residuewhich was purified by SCX or flash chromatography depending on the case.

General Procedure: Nitrile Hydrolysis to Carboxamide

A solution of the corresponding nitrile (1.0 equiv) in DMSO (0.2 Msolution) was treated with K₂CO₃ (0.5 equiv) and 33% H₂O₂ (1.0-2.0equiv) at 0° C. The reaction was monitored by TLC and more H₂O₂ wasadded if required. After 12 h, the reaction was poured into H₂O andextracted with ethyl acetate and the combined organic layers were washedtwice with water and brine. After drying over sodium sulfate andevaporation under vacuum the crude product was purified by silica gelchromatography using the appropriate eluant (typicallychloroform/ethanol/NH₄OH, 92.3/7/0.7) to afford the title compound as asolid.

General Procedure: Methanesulfonate Salt

To a solution of the corresponding organic compound (1.0 equiv) in THF(0.1 M solution) was treated with metanesulfonic acid (1 equiv) toafford the desired sulfonate salt after purification.

EXAMPLE 3106-[4-((2-Cyclopentyl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinamide

Step 16-[4-((2-Cyclopentyl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinonitrile

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

20% yield.

¹H NMR (MeOH-d₄) δ: 8.41 (dd, 1H, J=2.1, 0.5 Hz), 8.07 (dd, 1H, J=8.8,2.1 Hz), 7.15-6.90 (m, 4H), 4.01 (q, 2H, J=7.0 Hz), 3.77 (s, 2H), 2.63(t, 2H, J=7.0 Hz), 1.80 (m, 3H), 1.55 (m, 6H), 1.11 (m, 5H).

¹³C NMR (MeOH-d₄) δ: 166.2, 152.0, 151.0, 142.8, 141.3, 138.4, 122.5,121.1, 116.8, 114.3, 111.4, 104.0, 64.3, 53.2, 49.3, 38.4, 35.7, 32.1,25.1, 14.0.

MS (Electrospray): 366.5 (M⁺+1).

Step 2

The title compound may be prepared by basic hydsrolysis of the nitrilegroup to form the amide as has been described previously.

EXAMPLE 3116-[4-((3,3-Dimethyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinamide

Step 16-[4-((3,3-Dimethyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinonitrile

The above compound was obtained in quantitative yield following theapplicable general procedures described above and using thecorresponding intermediates and reagents.

¹H NMR (MeOH-d₄) δ: δ: 8.42 (dd, 1H, J=0.8, 2.4 Hz), 8.10 (dd, 1H,J=8.6, 2.4 Hz), 7.15-6.85 (m, 4H), 4.01 (q, 2H, J=7.0 Hz), 3.76 (s, 2H),2.65 (t, 2H, J=8.0 Hz), 1.43 (t, 2H, J=8.0 Hz), 1.12 (t, 3H, J=7.0 Hz),0.91 (s, 9H).

¹³C NMR (MeOH-d₄) δ: 165.8, 151.4, 150.5, 142.3, 140.7, 138.3, 122.0,113.8, 110.9, 103.5, 63.8, 52.9, 48.4, 44.6, 42.7, 28.5, 13.5.

MS (Electrospray): 354.2 (M⁺+1).

Step 2

The title amide may be obtained via basic hydrolysis reaction of thenitrile from step 1 following procedures described previously.

EXAMPLE 3126-[4-((3-Methyl-butylamino)-methyl)-2,5-dimethylphenoxy]nicotinamide

Step 16-[4-((3-Methyl-butylamino)-methyl)-2,5-dimethylphenoxy]nicotinonitrile

The above compound was obtained in quantitative yield following theapplicable general procedures described above and using thecorresponding intermediates and reagents.

¹H NMR (MeOH-d₄) δ: 8.43 (dd, 1H, J=2.4, 0.8 Hz), 8.11 (dd, 1H, J=8.6,2.4 Hz), 7.13-7.05 (m, 3H), 3.69 (s, 2H), 2.60 (t, 2H, J=7.0 Hz), 2.05(s, 6H), 1.65-1.51 (m, 1H), 1.51-1.35 (m, 2H), 0.90 (d, 6H, J=6.9 Hz).

¹³C NMR (MeOH-d₄) δ: 164.1, 151.0, 147.7, 141.9, 136.0, 129.3, 127.7,127.6, 115.3, 109.6, 102.7, 51.6, 47.5, 37.1, 25.1, 20.7, 14.0, 14.1.

MS (Electrospray): 324.5 (M⁺+1).

Step 2

The title amide may be obtained via basic hydrolysis reaction of thenitrile from step 1 following procedures described previously.

EXAMPLE 3136-[4-((2-Phenyl-ethylamino)-methyl)-2,5-dimethylphenoxy]nicotinamide

Step 16-[4-((2-Phenyl-ethylamino)-methyl)-2,5-dimethylphenoxy]nicotinonitrile

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.43 (dd, 1H, J=2.1, 0.5 Hz), 8.15 (dd, 1H, J=8.6,2.1 Hz), 7.35-7.05 (m, 8H), 3.71 (s, 2H), 2.82 (s, 4H), 2.04 (s, 6H).

¹³C NMR (MeOH-d₄) δ: 164.9, 151.9, 148.7, 142.8, 139.5, 136.7, 130.3,128.5, 128.2, 128.1, 125.8, 116.2, 110.5, 103.6, 52.2, 49.9, 35.2, 15.0.

MS (Electrospray): 358.1 (M⁺+1).

Step 2

The title amide may be obtained via basic hydrolysis reaction of thenitrile from step 1.

EXAMPLE 3146-[4-((2-Thiophen-2-yl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinamide

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

94% yield.

¹H NMR (MeOH-d₄) δ: 8.60 (d, 1H, J=2.2 Hz), 8.24 (dd, 1H, J=8.7, 2.4Hz), 7.21 (d, 1H, J=5.0 Hz), 7.11 (m, 2H), 7.00-6.90 (m, 4H), 4.15 (q,2H, J=6.8 Hz), 3.80 (s, 2H), 3.07 (t, 2H, J=7.5 Hz), 2.90 (t, 2H, J=7.5Hz), 1.11 (t, 3H, J=6.8 Hz).

¹³C NMR (MeOH-d₄) δ: 167.4, 164.9, 149.8, 146.2, 140.9, 138.1, 137.0,125.5, 123.8, 123.2, 122.2, 121.2, 119.7, 112.9, 108.6, 62.9, 51.6,49.0, 28.3, 12.6.

MS (Electrospray): 398.0 (M⁺+1).

EXAMPLE 3156-[4-((3-Methyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinamidemethanesulfonate salt

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.60 (s, 1H), 8.32 (dt, 1H, J=6.4, 2.2 Hz),7.35-7.01 (m, 4H), 4.26 (s, 2H), 4.06 (q, 2H, J=6.8 Hz), 3.14 (t, 2H,J=8.0 Hz), 2.72 (s, 3H), 1.80-1.60 (m, 3H), 1.14 (t, 3H, J=6.8 Hz), 1.00(d, 6H, J=6.0 Hz).

¹³C NMR (MeOH-d₄) δ: 166.8, 164.1, 150.0, 145.5, 141.8, 138.5, 128.7,123.4, 121.9, 121.2, 114.2, 109.0, 63.1, 49.5, 44.7, 37.1, 33.3, 24.7,20.1, 12.3.

MS (Electrospray): 358.5 (M⁺+1).

EXAMPLE 3166-[4-((3,3-Dimethyl-butylamino)-methyl)-2-ethoxyphenoxy]nicotinamide

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.60 (d, 1H, J=2.4 Hz), 8.24 (dt, 1H, J=8.6, 2.2Hz), 7.15 (m, 2H), 7.00-6.90 (m, 2H), 4.01 (q, 2H, J=7.0 Hz), 3.78 (s,2H), 2.65 (t, 2H, J=8.0 Hz), 1.49 (t, 2H, J=8.0 Hz), 1.12 (t, 3H, J=7.0Hz), 0.93 (s, 9H).

¹³C NMR (MeOH-d₄) δ: 167.3, 164.9, 149.7, 146.2, 140.3, 138.1, 137.1,123.2, 121.2, 119.7, 113.1, 108.6, 62.9, 52.0, 43.7, 41.8, 28.2, 27.6,12.6.

MS (Electrospray): 372.3 (M⁺+1).

EXAMPLE 317 6-[4-(Butylamino-methyl)-2-ethoxyphenoxy]nicotinamide

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.61 (d, 1H, J=2.4 Hz), 8.24 (dd, 1H, J=8.6, 2.4Hz), 7.14 (m, 2H), 7.00-6.90 (m, 2H), 4.01 (q, 2H, J=7.0 Hz), 3.78 (s,2H), 2.63 (t, 2H, J=7.2 Hz), 1.56 (m, 2H), 1.40 (m, 2H), 1.13 (t, 3H,J=7.0 Hz), 0.96 (t, 3H, J=7.0 Hz).

¹³C NMR (MeOH-d₄) δ: 167.3, 164.9, 149.7, 146.3, 140.3, 138.1, 137.1,123.3, 121.2, 119.7, 113.0, 108.6, 62.9, 51.9, 47.5, 30.2, 19.2, 12.6,12.0.

MS (Electrospray): 344.2 (M⁺+1).

EXAMPLE 3186-[4-((2-Phenyl-ethyamino)-methyl)-2,5-dimethylphenoxy]nicotinamide

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.61 (dd, 1H, J=2.4, 0.5 Hz), 8.24 (dd, 1H, J=8.6,2.4 Hz), 7.35-7.10 (m, 5H), 7.04 (s, 2H), 6.92 (dd, 1H, J=8.6, 0.5 Hz),3.70 (s, 2H), 2.82 (s, 4H), 2.05 (s, 6H).

¹³C NMR (MeOH-d₄) δ: 167.3, 164.0, 148.0, 146.8, 138.6, 135.6, 129.5,127.6, 127.2, 124.9, 123.3, 108.0, 51.4, 49.0, 34.3, 14.2.

MS (Electrospray): 376.1 (M⁺+1).

EXAMPLE 3196-[4-((2-Cyclopentyl-ethyamino)-methyl)-2-ethoxyphenoxy]nicotinamidemetanosulfonate salt

The above compound was obtained following the applicable generalprocedures described above and using the corresponding intermediates andreagents.

89% yield.

¹H NMR (MeOH-d₄) δ: 8.53 (dd, 1H, J=2.3, 0.5 Hz), 8.25 (dd, 1H, J=8.6,2.3 Hz), 7.28-7.21 (m, 2H), 7.25 (dd, 1H, J=8.3, 1.9 Hz), 7.05 (dd, 1H,J=8.6, 0.5 Hz), 4.21 (s, 2H), 4.01 (q, 2H, J=7.0 Hz), 3.08 (t, 2H, J=8.0Hz), 2.69 (s, 3H), 1.90-1.50 (m, 10H), 1.12 (m, 4H).

¹³C NMR (MeOH-d₄) δ: 167.2, 164.4, 150.3, 146.0, 142.3, 138.2, 128.5,123.6, 122.1, 121.2, 114.2, 109.1, 63.2, 49.7, 37.1, 36.3, 31.0, 30.9,23.6, 12.4.

MS (Electrospray): 384.2 (M⁺+1).

EXAMPLE 3206-[4-((3-Methyl-butylamino)-methyl)-2,5-dimethylphenoxy]nicotinonamide

62% yield.

¹H NMR (MeOH-d₄) δ: 8.56 (dd, 1H, J=2.4, 0.5 Hz), 8.23 (dd, 1H, J=8.6,2.4 Hz), 7.11 (s, 2H), 6.90 (dd, 1H, J=8.6, 0.5 Hz), 3.70 (s, 2H), 2.61(t, 2H, J=7.5 Hz), 2.07 (s, 6H), 1.75-1.51 (m, 1H), 1.51-1.35 (m, 2H),0.90 (d, 6H, J=6.5 Hz).

¹³C NMR (MeOH-d₄) δ: 167.3, 164.1, 148.0, 146.6, 138.6, 135.7, 129.5,127.7, 123.3, 108.1, 51.6, 45.8, 37.1, 25.1, 20.6, 14.1.

MS (Electrospray): 342.3 (M⁺+1).

3-Substituted Piperidine Series General Methods

Reagents obtained from commercial suppliers were used without furtherpurification unless otherwise noted. Solvents were purchased asanhydrous and used without further purification. All air and watersensitive reactions were performed in heat-dried glassware under anitrogen atmosphere. ¹H NMR spectra were recorded on a Varianspectrometer at 400 MHz using CD₃OD, CDCl₃, or DMSO-d₆. All preparativereverse-phase high-performance liquid chromatography (RP-HPLC) wasperformed using a Kromasil® column (50.8 mm×25 cm) with a gradient of95:5→20:80 0.03% aqueous hydrochloric acid:acetonitrile at 10 mL/minover 70 min. time. Analytical thin layer chromatography was performed onWhatman plates (2.5×7.5 mm) and visualized using para-anisaldehyde orpotassium permanganate stain followed by heating. Silica gelchromatography was performed using Biotage prepacked silica gel columns(KP-sil, 60 Å).

EXAMPLE 3216-[4-(1-Benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenoxy]-nicotinamidehydrochloride salt

Step 1 6-(4-Iodo-phenoxy)-nicotinamide

Combine 4-iodophenol (6.31 g, 28.7 mmol), 6-chloro-nicotinamide (4.51 g,28.8 mmol), potassium carbonate (10.0 g, 72.4 mmol), anddimethylacetamide (145 mL), stir and heat at 200° C. After 3 h, cool toambient temperature and dilute with water (600 mL), filter, and dry invacuo to provide 8.27 g (85%) of the title compound as a white/brownsolid: mass spectrum (electrospray): m/z=341.0 (M+1); ¹H NMR(methanol-d₄): 8.67 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz),7.82-7.79 (m, 2H). 7.09 (d, 1H, J=8.8 Hz), 7.03-6.99 (m, 2H).

Step 2

Combine bis(pinacolato)diboron (0.437 g, 1.72 mmol), potassium acetate(0.454 g, 4.62 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0273 g,0.0492 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.0377 g, 0.0461 mmol), flush with nitrogen, treat witha solution of trifluoro-methanesulfonic acid1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl ester (See Zheng, Q.; Yang, Y.;Martin, A. R. Tetrahedron Lett. 1993, 34, 2235-2238) (0.503 g, 1.56mmol) in dioxane (10 mL), stir and heat at 80° C. After 4 h, concentratethe reaction mixture and dry in vacuo. Combine crude boronate, potassiumcarbonate (0.650 g, 4.70 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.0777 g, 0.0951 mmol), treat with a solution of6-(4-iodo-phenoxy)-nicotinamide (0.582 g, 1.71 mmol) indimethylformamide (10 mL), stir and heat at 80° C. After 4.5 h, cool thereaction mixture to ambient temperature, dilute with water (30 mL), andextract with ethyl acetate (3×30 mL). Wash combined organic extractswith brine (1×) dry over anhydrous magnesium sulfate, filter, andconcentrate. Purify the residue by silica gel chromatography (10:1 to5:1 ethyl acetate:methanol), then reverse-phase HPLC to provide 0.175 g(29%) of the title compound as a white solid: mass spectrum(electrospray) m/z=386.2 (M+1); ¹H NMR (methanol-d₄): 8.66 (d, 1H, J=2.4Hz), 8.32 (dd, 1H, J=2.4, 8.3 Hz), 7.65-7.52 (m, 5H), 7.52-7.48 (m, 2H),7.22 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=8.8 Hz), 6.41 (m, 1H), 4.61 (d,1H, J=13.2 Hz), 4.52 (d, 1H, J=12.7 HZ), 4.22-4.20 (m, 2H), 3.72-3.67(m, 1H), 3.36-3.31 (m, 1H), 2.75-2.65 (m, 1H).

EXAMPLE 322 (±)-6-(4-Piperidin-3-yl-phenoxy)-nicotinamide hydrochloride

Combine the product of example 321 (0.0421 g, 0.0998 mmol), 10% Pd—C (2spatula tips), and methanol (2.0 mL). Bubble one balloon of hydrogen gasthrough solution then stir under ca. 1 atm. After 3.5 h, filter thereaction mixture through Celite®, concentrate, and purify byreverse-phase HPLC to provide 0.0129 g (39%) of the title compound as awhite solid: mass spectrum (electrospray): m/z=298.1 (M+1); ¹H NMR(methanol-d₄): 8.86 (s br, 1H), 8.59 (dd, 1H, J=2.0, 8.8 Hz), 7.53 (d,2H, J=8.3 Hz), 7.32 (d, 2H, J=7.8 Hz), 7.19 (d, 1H, J=8.8 Hz), 3.51 (d,1H, J=8.3 Hz), 3.25-3.08 (m, 3H), 2.18-2.08 (m, 2H), 2.06-1.84 (m, 2H).

EXAMPLE 323 (±)-6-[4-(1-Benzyl-piperidin-3-yl)-phenoxy]-nicotinamide

Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compoundof example 322) (0.0298 g, 0.101 mmol), benzaldehyde (0.0108 mL, 0.106mmol), and sodium triacetoxyborohydride (0.0310 mg, 0.146 mmol) inacetonitrile (2.0 mL). Add methanol (0.5 mL) to dissolve insolublestarting material. Add benzaldehyde (0.0200 mL, 0.197 mmol) after 15min. then stir for 4 h. Add sodium borohydride (0.0083 g, 0.219 mmol)and stir for 10 min., concentrate, and purify by silica gelchromatography (30:1 ethyl acetate:hexanes→20:1 ethyl acetate:methanol)to provide 0.0223 g (57%) of the title compound as a white solid: massspectrum (electrospray): m/z=388.2 (M+1); ¹H NMR (CDCl₃): 8.56 (d, 1H,J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.33-7.29 (m, 4H), 7.27-7.22(m, 3H), 5.84 (s br, 2H), 3.57 (m, 2H), 3.06-2.83 (m, 3H), 2.10-1.90 (m,4H), 1.80-1.70 (m, 2H), 1.50-1.37 (m, 1H).

EXAMPLE 324(±)-6-[4-(1-Cyclohexylmethyl-piperidin-3-yl)-phenoxy]-nicotinamide

Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compoundof example 322) (0.96 mL of 0.12 M stock solution in methanol, 0.0344 g,0.116 mmol) and cyclohexanecarboxaldehyde (0.021 mL, 0.173 mmol), andstir overnight. Add sodium borohydride (0.0108 g, 0.285 mmol), stir for4.5 h, then concentrate and purify by silica gel chromatography(20:1→10:1 ethyl acetate:methanol) to provide 0.0085 g (19%) of thetitle compound as a white solid: high resolution mass spectrum(electrospray): m/z calc for C₂₄H₃₂N₃O₂ 394.2495, found 394.2488; ¹H NMR(CDCl₃): 8.58 (s, 1H), 8.14 (d, 1H, J=7.8 Hz), 7.27 (d, 2H, J=8.3 Hz),7.05 (d, 2H, J=7.8 Hz), 6.93 (d, 1H, J=8.8 Hz), 5.89 (s br, 2H),2.99-2.77 (m, 3H), 2.16-2.06 (m, 2H), 1.97-1.83 (m, 3H), 1.80-1.59 (m,7H), 1.54-1.34 (m, 2H), 1.29-1.03 (m, 5H), 0.93-0.77 (m, 3H).

EXAMPLE 325 (±)-6-[4-(1-Methyl-piperidin-3-yl)-phenoxy]-nicotinamide

Combine 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compoundof example 322) (0.95 mL of 0.12 M stock solution in methanol, 0.0341 g,0.115 mmol) and formaldehyde (37% w/w in water, 0.014 mL, 0.156 mmol)and stir overnight. Add sodium borohydride (0.0128 g, 0.338 mmol) andstir. After 4.5 h concentrate the reaction mixture and purify by silicagel chromatography (20:1 ethyl acetate:methanol→2 M ammonia/methanol),then ion exchange chromatography (SCX resin, methanol→2 M ammonia (2M inmethanol) to provide 0.02215 g (60%) of the title compound as a whitesolid: high resolution mass spectrum (electrospray): m/z calc forC₁₈H₂₂N₃O₂ 312.1712, found 312.1718; ¹H NMR (methanol-d₄): 8.66 (d, 1H,J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.40-7.35 (m, 2H), 7.16-7.11(m, 2H), 7.02 (d, 1H, J=8.8 Hz), 3.10-3.02 (m, 2H), 2.92 (tt, 1H, J=3.4,11.7 Hz), 2.43 (s, 3H), 2.27-2.15 (m, 2H), 2.02-1.88 (m, 2H), 1.81 (qt,1H, J=3.9, 12.7 Hz), 1.57 (dq, 1H, J=3.9, 12.2 Hz).

EXAMPLE 326(±)-6-[4-(1-(3-Fluoro-benzyl)-piperidin-3-yl)-phenoxy]-nicotinamide

Using a method similar to Example 324,6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound ofexample 322) (0.98 mL of 0.12 M stock solution in methanol, 0.0343 g,0.115 mmol), 3-fluoro-benzaldehyde (0.0180 mL, 0.170 mmol), and sodiumborohydride (0.0102 g, 0.270 mmol) provide 0.0193 g (41%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₄H₂₅FN₃O₂ 406.1931, found 406.1917; ¹H NMR (CDCl₃): 8.56(d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.28-7.21 (m, 3H),7.09-7.02 (m, 4H), 6.95-6.88 (m, 2H), 5.74 (s br, 2H), 3.52 (d, 1H,J=13.7 Hz), 3.50 (d, 1H, J=13.7 Hz), 3.00-2.93 (m, 1H), 2.93-2.80 (m,2H), 2.06-1.90 (m, 3H), 1.80-1.64 (m, 2H), 1.44 (dq, 1H, J=4.4, 12.2Hz).

EXAMPLE 327(±)-6-[4-(1-(2-Fluoro-benzyl)-piperidin-3-yl)-phenoxy]-nicotinamide

Using a method similar to Example 324.6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound ofexample 322) (0.0305 g, 0.103 mmol), 2-fluoro-benzaldehyde (0.0160 mL,0.152 mmol), and sodium borohydride (0.0093 g, 0.246 mmol) provide0.0179 g (43%) of the title compound as a white foam: high resolutionmass spectrum (electrospray): m/z calc for C₂₄H₂₅FN₃O₂ 406.1931, found406.1936; ¹H NMR (CDCl₃): 8.56 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4,8.8 Hz), 7.37 (dt, 1H, J=1.9, 7.3 Hz), 7.27-7.18 (m, 3H), 7.09 (dt, 1H,J=1.0, 7.3 Hz), 7.06-6.97 (m, 3H), 6.93 (dd, 1H, J=1.0, 8.8 Hz), 5.71 (sbr, 2H), 3.56 (s, 2H), 3.04-2.97 (m, 1H), 2.93 (d, 1H, J=10.7 Hz), 2.85(tt, 1H, J=3.4, 11.2 Hz), 2.12-2.01 (m, 2H), 1.96-1.88 (m, 1H),1.81-1.64 (m, 2H), 1.41 (dq, 1H, J=4.4, 11.7 Hz).

EXAMPLE 328 (±)-6-[4-(1-Hexyl-piperidin-3-yl)-phenoxy]-nicotinamide

Using a method similar to Example 324,6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound ofexample 322) (0.0260 g, 0.0874 mmol), hexanal (0.0195 mL, 0.162 mmol),and sodium borohydride (0.0076 g, 0.200 mmol) provide 0.0100 g (30%) ofthe title compound as an off-white foam: high resolution mass spectrum(electrospray): m/z calc for C₂₃H₃₂N₃O₂ 382.2495, found 382.2513; ¹H NMR(methanol-d₄): 8.66 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz),7.41-7.35 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (d, 1H, J=8.3 Hz), 3.23-3.16(m, 2H), 2.95 (tt, 1H, J=3.4, 11.7 Hz), 2.63-2.56 (m, 2H), 2.35-2.22 (m,2H), 2.05-1.90 (m, 2H), 1.83 (tq, 1H, J=3.9, 13.7 Hz), 1.70-1.56 (m,3H), 1.45-1.30 (m, 6H), 0.96 (t, 3H, J=6.3 Hz).

EXAMPLE 329(±)-6-{4-[1-(3-Methyl-butyl)-piperidin-3-yl]-phenoxy}-nicotinamide

Using a method similar to Example 324,6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound ofexample 322) (0.0252 g, 0.0847 mmol), isovaleraldehyde (0.0165 mL, 0.154mmol), and sodium borohydride (0.0082 g, 0.217 mmol) provide 0.0100 g(32%) of the title compound as an off-white foam: high resolution massspectrum (electrospray): m/z calc for C₂₂H₃₀N₃O₂ 368.2338, found368.2355; ¹H NMR (methanol-d₄): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H,J=2.4, 8.8 Hz), 7.41-7.36 (m, 2H), 7.17-7.12 (m, 2H), 7.03 (d, 1H, J=8.8Hz), 3.28-3.19 (m, 2H), 2.96 (tt, 1H, J=3.4, 11.7 Hz), 2.71-2.63 (m,2H), 2.43-2.28 (m, 2H), 2.06-1.92 (m, 2H), 1.84 (qt, 1H, J=3.9, 13.2Hz), 1.71-1.51 (m, 4H), 0.99 (d, 6H, J=6.3 Hz).

EXAMPLE 330 (±)-6-[4-(1-Phenethyl-piperidin-3-yl)-phenoxy]-nicotinamide

Combine 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (compound of example322) (0.0237 g, 0.0797 mmol), (2-bromoethyl)benzene (0.0108 mL, 0.0791mmol), and potassium carbonate (0.0237 g, 0.171 mmol) indimethylformamide (0.96 mL) and stir for 15 min. Then purify thereaction mixture by ion exchange chromatography (SCX resin, methanol→2 Mammonia in methanol) to provide 0.0204 g (64%) of the title compound asan off-white foam: high resolution mass spectrum (electrospray): m/zcalc for C₂₅H₂₈N₃O₂ 402.2182, found 402.2182; ¹H NMR (methanol-d₄): 8.66(d, 1H, J=2.0 Hz), 8.28 (dd, 1H, J=2.9, 8.3 Hz), 7.37 (d, 2H, J=7.8 Hz),7.33-7.27 (m, 2H), 7.27-7.18 (m, 3H), 7.12 (d, 2H, J=8.3 Hz), 7.01 (d,1H, J=8.8 Hz), 3.15 (d, 2H, J=11.2 Hz), 2.97-2.85 (m, 3H), 2.73-2.65 (m,2H), 2.19 (q, 2H, J=11.2 Hz), 2.03-1.74 (m, 3H), 1.59 (dq, 1H, J=4.4,12.7 Hz).

EXAMPLE 331(±)-6-{4-[1-(2-Cyclohexyl-ethyl)-piperidin-3-yl]-phenoxy}-nicotinamide

Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base compound ofexample 322) (0.0255 g, 0.0858 mmol), 1-bromo-2-cyclohexylethane (0.0150mL, 0.0958 mmol), and potassium carbonate (0.0245 g, 0.177 mmol) indimethylformamide (1.0 mL) and stir for 10 min. Purify the reactionmixture by ion exchange chromatography (SCX resin, methanol→2 Mammonia/methanol) and silica gel chromatography (15:1→10:1 ethylacetate:methanol) to provide 0.0146 g (42%) of the title compound as anoff-white foam: high resolution mass spectrum (electrospray): m/z calcfor C₂₅H₃₄N₃O₂ 408.2651, found 408.2661; ¹H NMR (methanol-d₄): 8.61 (sbr, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.36 (d, 2H, J=7.8 Hz), 7.12 (d, 2H,J=7.8 Hz), 7.01 (d, 1H, J=8.3 Hz), 3.07 (d, 2H, J=10.2 Hz), 2.89 (t, 1H,J=11.2 Hz), 2.55-2.42 (m, 2H), 2.15-1.93 (m, 4H), 1.93-1.64 (m, 8H),1.63-1.43 (m, 4H), 1.40-1.15 (m, 8H), 1.07-0.86 (m, 3H).

EXAMPLE 332 6-[4-(4-Benzyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Step 1 6-(4-Formyl-phenoxy)-nicotinamide

Combine 4-hydroxy benzaldehyde (7.201 g, 59.0 mmol),6-chloronicotinamide (9.605 g, 57.5 mmol), and potassium carbonate(19.86 g, 143.7 mmol) in dimethylacetamide (190 mL). Stir and heat at130° C. After 18 h, cool to ambient temperature and dilute with water(600 mL). Extract aqueous layer with ethyl acetate (3×500 mL). Washcombined ethyl acetate extracts with water (1×) and brine (1×),successively, dry over anhydrous magnesium sulfate, filter, andconcentrate. Purification by silica gel chromatography (1:1 ethylacetate:hexanes→ethyl acetate) to provide 6.852 g (49%, 90% pure) of thetitle compound as a white solid: mass spectrum (electrospray): m/z=243.0(M+1); ¹H NMR (methanol-d₄): 9.97 (s, 1H), 8.70 (d, 1H, J=2.4 Hz), 8.36(dd, 1H, J=2.4, 8.8 Hz), 8.06-8.02 (m, 2H), 7.42-7.37 (m, 2H), 7.19 (d,1H, J=9.3 Hz).

Step 2 6-[4-(4-Benzyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 6-(4-formyl-phenoxy)-nicotinamide (from step 1 above) (0.300 g,1.24 mmol) and 1-benzylpiperazine (0.35 mL, 2.01 mmol) in methanol (12mL) and stir at ambient temperature. After 15 h, add sodium borohydride(0.108 g, 2.85 mmol) and stir. After 1 h, filter the white precipitateand dry under vacuum to give 0.283 g (57%) of the title compound as awhite solid: high resolution mass spectrum (electrospray): m/z calc forC₂₄H₂₇N₄O₂ 403.2134, found 403.2128: ¹H NMR (DMSO-d₆): 8.63 (d, 1H,J=1.5 Hz), 8.27 (dd, 1H, J=2.4, 8.3 Hz), 8.05 (s br, 1H) 7.50 (s br,1H), 7.39-7.23 (m, 7H), 7.15-7.06 (m, 3H), 3.48 (m, 4H), 2.41 (s br,8H).

EXAMPLE 3336-[4-(4-Phenethyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 332, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.304 g, 1.26 mmol), 1-(2-phenethyl)piperazine (0.360 g, 1.89 mmol),and sodium borohydride (0.109 g, 2.88 mmol) in methanol (10 mL) provides0.246 g (47%) of the title compound as a white solid: high resolutionmass spectrum (electrospray): m/z calc for C₂₅H₂₉N₄O₂ 417.2291, found417.2291; ¹H NMR (DMSO-d₆): 8.60 (d, 1H, J=2.4 Hz), 8.23 (dd, 1H, J=2.4,8.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.28-7.21 (m, 2H), 7.21-7.12 (m, 3H),7.08 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=8.8 Hz), 3.45 (s, 2H), 2.74-2.62(m, 2H), 2.52-2.26 (m, 10H).

EXAMPLE 3346-[4-(4-Cyclopentyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332,step 1) (0.303 g, 1.25 mmol) and 1-cyclopentyl piperazine (0.198 g, 1.28mmol) in methanol (11 mL) and stir. After 15.5 h, add sodium borohydride(0.109 g, 2.88 mmol), and stir at ambient temperature. After 1 h,concentrate the reaction mixture and purify by silica gel chromatography(ethyl acetate→4:1 ethyl acetate:methanol) to provide 0.172 g (36%) ofthe title compound as an off white solid: high resolution mass spectrum(electrospray): m/z calc for C₂₂H₂₉N₄O₂ 381.2291, found 381.2306; ¹H NMR(DMSO-d₆): 8.66 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.9, 8.8 Hz),7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 3.61 (s,2H), 3.00-2.25 (m, 9H), 2.01-1.88 (m, 2H), 1.82-1.69 (m, 2H), 1.69-1.56(m, 2H), 1.53-1.38 (m, 2H).

EXAMPLE 335(±)-6-{4-[4-(1-Phenyl-ethyl)-piperazin-1-ylmethyl]-phenoxy}-nicotinamide

Using a method similar to Example 332, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.307 g, 1.27 mmol), 1-(1-phenylethyl)piperizine (0.365 g, 1.92 mmol),and sodium borohydride (0.108 g, 2.85 mmol) in methanol (10 mL), after 1d, provides 0.122 g (23%) of the title compound as a white solid: highresolution mass spectrum (electrospray): m/z calc for C₂₅H₂₉N₄O₂417.2291, found 417.2298; ¹H NMR (DMSO-d₆): 8.62 (d, 1H, J=2.0 Hz), 8.26(dd, 1H, J=2.4, 8.8 Hz), 8.01 (s br, 1H), 7.46 (s br, 1H), 7.36-7.28 (m,6H), 7.27-7.21 (m, 1H), 7.12-7.05 (m, 3H), 3.42 (s, 2H), 3.39 (q, 1H,J=6.8 Hz), 2.51-2.25 (s br, 8H), 1.29 (d, 3H, J=6.8 Hz).

EXAMPLE 3366-[4-(4-Benzhydryl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 334, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.300 g, 1.24 mmol), 1-benzhydryl-piperazine (0.470 g, 1.86 mmol), andsodium borohydride (0.111 g, 2.93 mmol) in methanol (12 mL), afteradditional purification by reverse-phase HPLC, provides 0.143 g (24%) ofthe title compound as a yellow foam: high resolution mass spectrum(electrospray): m/z calc for C₃₀H₃₁N₄O₂ 479.2447, found 479.2462; ¹H NMR(methanol-d₄): 8.65 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz),7.49-7.42 (m, 6H), 7.30 (t, 4H, J=7.8 Hz), 7.23-7.17 (m, 2H), 7.14 (d,2H, J=8.8 Hz), 7.03 (d, 1H, J=8.8 Hz), 4.28 (s, 1H), 3.63 (s, 2H),2.72-2.30 (m, 8H).

EXAMPLE 3376-{4-[4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl]-phenoxy}-nicotinamide

Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332,step 1) (0.299 g, 1.23 mmol), 1-(4-fluoro-phenyl)-piperizine, bishydrochloride salt (0.314 g, 1.24 mmol), triethylamine (0.36 mL, 2.58mmol) in methanol (12 mL) and stir. After 23 h, add sodium borohydride(0.108 g, 2.85 mmol). After 1 d, concentrate and purify the residue bysilica gel chromatography (25:1→4:1 methylene chloride:methanol) toprovide 0.107 g (21%) of the title compound as a white solid: highresolution mass spectrum (electrospray): m/z calc for C₂₃H₂₄FN₄O₂407.1883, found 407.1883; ¹H NMR (methanol-d₄): 8.67 (d, 1H, J=2.4 Hz),8.30 (dd, 1H, J=2.4, 8.8 Hz) 7.52-7.47 (m, 2H), 7.20-7.15 (m, 2H), 7.05(d, 1H, J=7.8 Hz), 7.01 (d, 4H, J=6.3 Hz), 3.66 (s, 2H), 3.21-3.16 (m,4H), 2.74-2.68 (m, 4H).

EXAMPLE 338 6-[4-(4-Phenyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 334, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.302 g, 1.25 mmol), 1-phenyl-piperazine (0.192 mL, 1.26 mmol), andsodium borohydride (0.110 g, 2.91 mmol) in methanol (12 mL) provides0.0627 g (13%) of the title compound as a white solid Chromatographysolvent: 25:1 methylene chloride:methanol. High resolution mass spectrum(electrospray): m/z calc for C₂₃H₂₅N₄O₂ 389.1978, found 389.1993; ¹H NMR(methanol-d₄): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.9, 8.8 Hz),7.50 (d, 2H, J=8.8 Hz), 7.27 (dd, 2H, J=7.3, 8.8 Hz), 7.20-7.15 (m, 2H),7.05 (d, 1H, J=8.3 Hz), 7.03-6.99 (m, 2H), 6.88 (t, 1H, J=7.3 Hz), 3.67(s, 2H), 3.27-3.21 (m, 4H), 2.74-2.69 (m, 4H).

EXAMPLE 3396-[4-(4-Cyclohexyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 334, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.299 g, 1.23 mmol), 1-cyclohexyl-piperazine (0.208 g, 1.24 mmol), andsodium borohydride (0.107 g, 2.83 mmol) in methanol (12 mL) provides0.158 g (32%) of the title compound as a white solid (chromatographysolvent: 20:1→10:1 methylene chloride:methanol). High resolution massspectrum (electrospray): m/z calc for C₂₃H₃₁N₄O₂ 395.2447, found395.2461; ¹H NMR (methanol-d₄): 8.66 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H,J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3Hz), 3.61 (s, 2H), 2.82-2.53 (m, 8H), 2.39-2.29 (m, 1H), 2.03-1.96 (m,2H), 1.91-1.83 (m, 2H), 1.73-1.66 (m, 1H), 1.40-1.15 (m, 5H).

EXAMPLE 3406-[4-(4-Isopropyl-piperazin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 334, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.304 g, 1.26 mmol), 1-isopropyl-piperazine (0.161 g, 1.26 mmol), andsodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides0.158 g (32%) of the title compound as a white solid (chromatographysolvent: ethyl acetate→7:3 ethyl acetate:methanol): high resolution massspectrum (electrospray): m/z calc for C₂₀H₂₇N₄O₂ 355.2134, found355.2140; ¹H NMR (methanol-d₄): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H,J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3Hz), 3.56 (s, 2H), 2.79-2.52 (m, 9H), 1.13 (d, 6H, J=6.8 Hz).

EXAMPLE 341(3R)-6-{4-[(1-Benzyl-pyrrolidin-3-ylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 334, using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.300 g, 1.24 mmol), (3R)-1-benzylpyrrolidin-3-yl amine (0.22 mL, 1.27mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL)provides 0.154 g (31%) of the title compound as a white foam(chromatography solvent:ethyl acetate→4:1 ethyl acetate:methanol): highresolution mass spectrum (electrospray): m/z calc for C₂₄H₂₇N₄O₂403.2134, found 403.2131; ¹H NMR (methanol-d₄): 8.66 (d, 1H, J=2.4 Hz),8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H),7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76(d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz),3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t 2H, J=6.8 Hz),2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).

EXAMPLE 342(3S)-6-(4-[(1-Benzyl-pyrrolidin-3-ylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 334, and using6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.300 g, 1.24 mmol), (3S)-1-benzylpyrrolidin-3-yl amine (0.21 mL, 1.22mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL)provides 0.214 g (43%) of the title compound as a white foam(chromatography solvent: ethyl acetate→19:1 ethyl acetate:methanol):high resolution mass spectrum (electrospray): m/z calc for C₂₄H₂₇N₄O₂403.2134, found 403.2144; ¹H NMR (methanol-d₄): 8.66 (d, 1H, J=2.4 Hz),8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H),7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3. Hz), 3.79 (d, 1H, J=13.2 Hz),3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t, 2H, J=6.8Hz). 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m,1H).

EXAMPLE 343 (±)-6-[4-(2-Phenyl-piperidin-ylmethyl)-phenoxy]-nicotinamide

Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332,step 1) (0.152 g, 0.628 mmol), 2-phenyl-piperidine hydrochloride salt(0.122 g, 0.620 mmol), triethylamine (0.178 mL, 1.28 mmol) in methanol(6.0 mL) and stir. After 21 hours, add sodium borohydride (0.108 g, 2.85mmol). After about 24 hours, concentrate and purify the residue bysilica gel chromatography (25:1→4:1 methylene chloride:methanol) thenreverse-phase HPLC to provide 0.0047 g (2%) of the title compound as awhite solid: mass spectrum (electrospray): m/z=388.2 (M+1); ¹H NMR(methanol-d₄): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.3 Hz),7.52 (d, 2H, J=7.3 Hz), 7.41 (t, 2H, J=7.3 Hz), 7.37-7.28 (m, 3H), 7.11(d, 2H, J=8.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 3.81 (d, 1H, J=10.7 Hz), 3.39(s, 2H), 3.20-2.94 (m, 2H), 2.17 (s br, 1H), 1.93-1.61 (m, 4H),1.59-1.44 (m, 1H).

EXAMPLE 344(±)-6-[4-(2-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamidehydrochloride

Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332,step 1) (0.150 g, 0.619 mmol), 2-phenyl-pyrrolidine (0.095 g, 0.64mmol), sodium triacetoxyborohydride (0.194 g, 0.915 mmol), and aceticacid (0.051 mL, 0.891 mmol) in 1,2-dichloroethane (9.0 mL). After about24 hours, purify the reaction mixture by ion exchange chromatography(SCX resin, methanol→2 M ammonia/methanol) and concentrate. Dissolve theresidue in 1,4-dioxane and treated with 4 N hydrochloric acid indioxane. Isolate the white precipitate by vacuum filtration. The solidbecame a yellowish syrup after approximately 3 min. on vacuum. Dissolvethe residue in 1,4-dioxane and concentrate to provide 0.0100 g (3.9%) ofthe title compound as a white/yellow foam: high resolution mass spectrum(electrospray): m/z calc for C₂₃H₂₄N₃O₂ 374.1869, found 374.1877; ¹H NMR(methanol-d₄): 8.63 (s, 1H), 8.35 (dd, 1H, J=1.5, 7.8 Hz), 7.64-7.44 (m,7H), 7.24 (d, 2H, J=8.8 Hz), 7.11 (d, 1H, J=8.8 Hz), 4.69-4.60 (m, 1H),4.28 (s, 2H), 3.75-3.66 (m, 1H), 3.58-3.47 (m, 1H), 2.71-2.60 (m, 1H),2.45-2.22 (m, 3H).

EXAMPLE 345(±)-6-[4-(3-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Convert 3-phenyl-pyrrolidine phosphoric acid salt (0.152 g, 1.03 mmol)to the free base by ion exchange chromatography (SCX resin, methanol→2 Mammonia/methanol) and then concentrate. Combine free base with6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.150 g, 0.618 mmol), sodium triacetoxyborohydride (0.201 g, 0.948mmol), and acetic acid (0.053 mL, 0.891 mmol) in 1,2-dichloroethane (9.5mL) and stir at ambient temperature. After 1 d, purify the reactionmixture by ion exchange chromatography (SCX resin, methanol→2 M ammoniain methanol) and concentrate to provide 0.204 g (88%) of the titlecompound as a white solid: high resolution mass spectrum (electrospray):m/z calc for C₂₃H₂₄N₃O₂ 374.1869, found 374.1887; ¹H NMR (methanol-d₄):8.67 (dd, 1H, J=1.0, 2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.52-7.47(m, 2H), 7.34-7.28 (m, 4H), 7.25-7.14 (m, 3H), 7.03 (dd, 1H, J=1.0, 8.8Hz), 3.80 (d, 1H, J=13.2 Hz), 3.77 (d, 1H, J=12.7 Hz), 3.48-3.38 (m,1H), 3.16 (dd, 1H, J=7.8, 9.3 Hz), 3.00-2.93 (m, 1H), 2.85-2.77 (m, 1H),2.58 (t, 1H, J=8.8 Hz), 2.44-2.32 (m, 1H), 2.02-1.91 (m, 1H).

EXAMPLE 346 6-[4-(4-Phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 342, using 4-phenyl-piperidinehydrochloride salt (0.0823 g, 0.416 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.136 g, 0.642mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0mL) provides 0.150 g (94%) of the title compound as a white solid: highresolution mass spectrum (electrospray): m/z calc for C₂₄H₂₆N₃O₂388.2025, found 388.2039; ¹H NMR (methanol-d₄): 8.67 (d, 1H, J=2.6 Hz),8.30 (dd, 1H, 2.6, 8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.35-7.25 (m, 4H),7.23-7.15 (m, 3H), 7.05 (d, 1H, J=8.8 Hz), 3.65 (s, 2H), 3.12 (d, 2H,J=11.9 Hz), 2.65-2.54 (m, 1H), 2.24 (dt, 2H, J=4.0, 11.0 Hz), 1.94-1.78(m, 4H).

EXAMPLE 347 (±)-6-[4-(3-Phenyl-azepan-1-ylmethyl)-phenoxy-nicotinamide

Using a method similar to Example 345, using 3-phenyl-azepane fumaricacid salt (0.122 g, 0.419 mmol), 6-(4-formyl-phenoxy)-nicotinamide(compound of example 332, step 1) (0.100 g, 0.415 mmol), sodiumtriacetoxyborohydride (0.129 g, 0.609 mmol), and acetic acid (0.034 mL,0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.154 g (93%) of thetitle compound as a white solid: high resolution mass spectrum(electrospray): m/z calc for C₂₅H₂₈N₃O₂ 402.2182. found 402.2199; ¹H NMR(DMSO-d₆): 8.61 (d, 1H, J=1.8 Hz), 8.25 (dd, 1H, J=2.6, 8.8 Hz) 8.02 (s,1H), 7.47 (s, 1H). 7.38 (d, 2H, J=8.4 Hz), 7.27-7.02 (m, 8H), 3.70 (d,1H, J=13.5 Hz), 3.64 (d, 1H, J=13.5 Hz), 2.89-2.63 (m, 5H), 1.81-1.59(m, 6H).

EXAMPLE 348 (±)-6-[4-(4-Phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3-phenyl-azepanehydrochloric acid salt (0.0874 g, 0.413 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.131 g, 0.618mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0mL) provides, after silica gel chromatography (20:1→10:1 methylenechloride:methanol), 0.0368 g (22%) of the title compound as a whitesolid: high resolution mass spectrum (electrospray): m/z calc forC₂₅H₂₈N₃O₂ 402.2182, found 402.2195; ¹H NMR (methanol-d₄): 8.67 (d, 1H,J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 9.3 Hz), 7.52 (d, 2H, J=7.3 Hz),7.33-7.23 (m, 4H), 7.22-7.15 (m, 3H), 7.06 (d, 1H, J=8.8 Hz), 3.84 (s,2H), 3.08-2.77 (m, 5H), 2.05-1.78 (m, 6H).

EXAMPLE 3496-[4-(4,4-Diphenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 4,4-diphenyl-piperidine(0.100 g, 0.421 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound ofexample 332, step 1) (0.102 g, 0.419 mmol), sodium triacetoxyborohydride(0.133 g, 0.627 mmol), and acetic acid (0.038 mL, 0.664 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(20:1 methylene chloride:methanol), 0.0871 g (45%) of the title compoundas a white solid: high resolution mass spectrum (electrospray): m/z calcfor C₃₀H₃₀N₃O₂ 464.2338, found 464.2357; ¹H NMR (methanol-d₄): 8.67 (d,1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.0, 7.8 Hz), 7.43 (d, 2H, J=7.8 Hz),7.38-7.27 (m, 8H), 7.19-7.11 (m, 4H), 7.02 (d, 1H, J=8.8 Hz), 3.55-3.50(m, 2H), 2.71-2.51 (m, 8H).

EXAMPLE 3506-[4-(3,3-Diphenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3,3-diphenyl-pyrrolidinehydrochloride salt (0.107 g, 0.412 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.133 g, 0.628mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0mL) provides 0.196 g (106%) of the title compound as a white solid: highresolution mass spectrum (electrospray): m/z calc for C₂₉H₂₈N₃O₂450.2182, found 450.2205; ¹H NMR (methanol-d₄): 8.68 (d, 1H, J=2.4 Hz),8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.46 (d, 2H, J=7.3 Hz), 7.35-7.26 (m, 8H),7.21-7.12 (m, 4H), 7.04 (d, 1H, J=8.8 Hz), 3.75 (s, 2H), 3.38-3.24 (m,2H), 2.98-2.91 (m, 2H), 2.71-2.64 (m, 2H).

EXAMPLE 3516-[4-(2,2-Diphenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3,3-diphenyl-pyrrolidinehydrochloride salt (0.108 g, 0.416 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.132 g, 0.623mmol), and acetic acid (0.035 mL 0.611 mmol) in 1,2-dichloroethane (8.0mL) provides, after silica gel chromatography (20:1 methylenechloride:methanol), 0.0646 g (34%) of the title compound as a whitesolid: high resolution mass spectrum (electrospray): m/z calc forC₂₉H₂₈N₃O₂ 450.2182, found 450.2204; ¹H NMR (methanol-d₄): 8.67 (d, 1H,J=2.4 Hz), 8.29 (dd, 1H, J=2.0, 8.3 Hz), 7.50 (d, 2H, J=8.3 Hz),7.44-7.35 (m, 8H), 7.34-7.27 (m, 2H), 7.15 (d, 2H, J=8.8 Hz), 7.03 (d,1H, J=7.8 Hz), 3.30 (s, 2H), 2.70 (t, 2H, J=6.8 Hz), 2.54-2.45 (m, 2H),2.11-1.99 (m, 2H).

EXAMPLE 352 6-(4-Piperidin-1-ylmethyl-phenoxy)-nicotinamide

Using a method similar to Example 345, using piperidine (0.041 mL, 0.414mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332,step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.131 g,0.618 mmol), and acetic acid (0.036 mL, 0.629 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(10:1→3:1 methylene chloride:methanol), 0.114 g (88%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₁₈H₂₂N₃O₂ 312.1712, found 312.1722, ¹H NMR (DMSO-d₆): 8.63(d, 1H, J=2.0 Hz), 8.27 (dd, 1H, J=2.4, 8.8 Hz), 8.06 (s br, 1H), 7.50(s br, 1H), 7.35 (a, 2H, J=8.3 Hz), 7.15-7.06 (m, 3H), 3.44 (s, 2H),2.35 (s, 4H), 1.57-1.48 (m, 4H), 1.46-1.36 (m, 2H).

EXAMPLE 353(±)-6-[4-(1,2,4,4a,9,9a-Hexahydro-3-aza-fluoren-3-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using4-(1,2,4,4a,9,9a-hexahydro-3-aza-fluorene hydrochloric acid salt (0.0866g. 0.413 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example332, step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.131g, 0.618 mmol), and acetic acid (0.034 mL, 0.594 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(20:1→10:1 methylene chloride:methanol), 0.0966 g (58%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₅H₂₆N₃O₂ 400.2025, found 400.2049; ¹H NMR (DMSO-d₆): 8.64(d, 1H, J=2.4 Hz), 8.27 (dd, 1H, J=2.0, 7.8 Hz), 8.05 (s br, 1H), 7.50(s br, 1H), 7.36-7.30 (m, 2H), 7.27-7.22 (m, 1H), 7.16-7.06 (m, 6H),3.53-3.43 (m, 2H), 3.13 (q, 1H, J=5.9 Hz), 2.86 (dd, 1H, J=6.8, 15.6Hz), 2.72-2.60 (m, 2H), 2.58-2.50 (m, 1H), 2.48-2.39 (m, 2H), 2.31-2.22(m, 1H), 1.76-1.67 (m, 1H), 1.45-1.34 (m, 1H).

EXAMPLE 354(±)-6-{4-[3-(2-Chloro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide

Using a method similar to Example 345, 3-(2-chloro-phenyl)-piperidinefumaric acid salt (0.128 g, 0.410 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.129 g 0.609mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0mL) provides, after silica gel chromatography (20:1→10:1 methylenechloride:methanol) and reverse-phase HPLC, 0.109 g (62%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₄H₂₅ClN₃O₂ 422.1635, found 422.1664; ¹H NMR(methanol-d₄): 8.67 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.2, 8.3 Hz),7.47 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=7.9 Hz), 7.30 (t, 1H, J=7.0 Hz),7.21 (dt, 1H, J=1.3, 7.5 Hz), 7.16 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=8.3Hz), 3.71 (d, 1H, J=13.2 Hz), 3.67 (d, 1H, J=13.6 Hz), 3.43 (tt, 1H,J=3.5, 11.9 Hz), 3.12-3.03 (m, 2H). 2.25-2.11 (m, 2H), 1.98-1.76 (m,3H), 1.58 (dq, 1H, J=4.8, 11.9 Hz).

EXAMPLE 355(±)-6-{4-[3-(3-Chloro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide

Using a method similar to Example 345, using3-(3-chloro-phenyl)-piperidine fumaric acid salt (0.129 g, 0.414 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.132 g, 0.623mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0mL) provides, after reverse-phase HPLC, 0.129 g (70%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₄H₂₅ClN₃O₂ 422.1635, found 422.1664; ¹H NMR(methanol-d₄): 8.66 (d, 1H, J=2.6 Hz), 8.30 (dd, 1H, J=2.6, 8.8 Hz),7.47 (d, 2H, J=8.8 Hz), 7.34-7.27 (m, 2H), 7.26-7.19 (m, 2H), 7.16 (d,2H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 3.70 (s, 2H), 3.07 (d, 2H, J=11.4Hz), 2.89 (tt, 1H, J=4.0, 11.9 Hz), 2.29-2.16 (m, 2H), 2.00-1.72 (m,3H), 1.56 (dq, 1H, J=4.0, 12.3 Hz).

EXAMPLE 356(±)-6-{4-[3-(3-Trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamide

Using a method similar to Example 345, using3-(3-trifluoromethyl-phenyl)-piperidine, hydrochloric acid salt (0.110g, 0.414 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example332, step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.130g, 0.613 mmol), and acetic acid (0.035 mL, 0.611 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(25:1 methylene chloride:methanol), 0.142 g (75%) of the title compoundas a white foam: high resolution mass spectrum (electrospray): m/z calcfor C₂₅H₂₅F₃N₃O₂ 456.1899, found 456.1903; ¹H NMR (methanol-d₄): 8.66(d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.3 Hz), 7.59-7.51 (m, 4H),7.49-7.44 (m, 2H), 7.18-7.12 (m, 2H), 7.04 (d, 1H, J=9.3 Hz), 3.69-3.61(m, 2H), 3.08-2.93 (m, 3H), 2.25-2.13 (m, 2H), 2.02-1.93 (m, 1H),1.91-1.72 (m, 2H), 1.59 (dq, 1H, J=4.4, 12.2 Hz).

EXAMPLE 357(±)-6-[4-(3-Methyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3-methyl-piperidine (0.0420g, 0.423 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.129g, 0.610 mmol), and acetic acid (0.035 mL, 0.611 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(10:1→7:3 methylene chloride:methanol), 0.0400 g (29%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₁₉H₂₄N₃O₂ 326.1869, found 326.1841; ¹H NMR (DMSO-d₆): 8.66(d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.5, 8.4 Hz), 8.06 (s br, 1H), 7.53(s br, 1H), 7.38 (d, 2H, J=8.4 Hz), 7.17-7.09 (m, 3H), 3.38-3.28 (m,2H), 2.83-2.70 (m, 2H), 1.95 (t, 1H, J=10.6 Hz), 1.74-1.41 (m, 5H),0.97-0.79 (m, 4H).

EXAMPLE 358(±)-6-[4-(3-Phenethyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3-phenethyl-piperidine(0.0789 g, 0.417 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound ofexample 332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride(0.129 g, 0.610 mmol), and acetic acid (0.038 mL, 0.664 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(25:1→8:1 methylene chloride:methanol), 0.085 g (49%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₆H₃₀N₃O₂ 416.2338, found 416.2346; ¹H NMR (methanol-d₄):8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.44 (d, 2H, J=8.3Hz), 7.30-7.24 (m, 2H), 7.20-7.13 (m, 5H), 7.05 (d, 1H, J=7.8 Hz), 3.60(s, 2H), 3.02-2.90 (m, 2H), 2.71-2.59 (m, 2H), 2.05 (dt, 1H, J=2.0, 11.2Hz), 1.89 (d, 1H, J=12.2 Hz), 1.82-1.69 (m, 2H), 1.68-1.52 (m, 4H), 1.00(dq, 1H, J=3.4, 12.2 Hz).

EXAMPLE 359(±)-6-[4-(3-Phenpropyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3-phenylpropyl-piperidine(0.0993 g, 0.414 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound ofexample 332, step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride(0.129 g, 0.610 mmol), and acetic acid (0.038 mL, 0.664 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(15:1→8:1 methylene chloride:methanol), 0.0977 g (55%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₇H₃₂N₃O₂ 430.2495, found 430.2511; ¹H NMR (methanol-d₄):8.66 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz), 7.55-7.49 (m, 2H),7.31-7.15 (m, 7H), 7.09 (d, 1H, J=8.8 Hz), 3.94 (d, 1H, J=13.2 Hz), 3.91(d, 1H, J=12.7 Hz), 3.18 (d, 2H, J=11.2 Hz), 2.63 (t, 2H, J=7.8 Hz),2.42 (dt, 1H, J=2.4, 12.2 Hz), 2.14 (t, 1H, J=11.7 Hz), 1.94-1.80 (m,2H), 1.80-1.59 (m, 4H), 1.38-1.26 (m, 2H), 1.04 (dq, 1H, J=4.4, 13.2Hz).

EXAMPLE 360(±)-6-[4-(3-Benzyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Step 1 (±)-3-Benzyl-piperidine

Combine 3-benzyl-pyridine (0.524 g, 3.10 mmol) and 10% palladium oncarbon (0.165 g) in acetic acid (30 mL) and stir at 60° C. at a H₂pressure of 60 psi. After 6 h, purify the reaction mixture by ionexchange chromatography (SCX resin, methanol→2 M ammonia/methanol) andsilica gel chromatography (10:1→3:1 methylene chloride:methanol) toprovide 0.225 g (42%) of the title compound as a yellow oil: ¹H NMR(DMSO-d₆): 7.28 (t, 2H, J=7.3 Hz), 7.22-7.13 (m, 3H), 3.01 (s br, 1H),2.87-2.76 (m, 2H), 2.50-2.34 (3H), 2.16 (dd, 1H, J=9.3, 11.7 Hz),1.70-1.49 (m, 3H), 1.29 (tq, 1H, J=3.9, 12.7 Hz), 1.03 (dq, 1H, J=3.9,12.7 Hz).

Step 2

Using a method similar to Example 345, using 3-benzyl-piperidine (0.0748g, 0.427 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.130g, 0.613 mmol), and acetic acid (0.035 mL, 0.611 mmol) in1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography(15:1→8:1 methylene chloride:methanol), 0.0626 g (37%) of the titlecompound as a white foam: high resolution mass spectrum (electrospray):m/z calc for C₂₅H₂₈N₃O₂ 402.2182, found 402.2192; ¹H NMR (methanol-d₄):8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.3 Hz), 7.42 (d, 2H, J=8.8Hz), 7.28 (t, 2H, J=7.3 Hz), 7.22-7.11 (m, 5H), 7.01 (d, 1H, J=8.3 Hz),3.62 (d, 1H, J=12.7 Hz), 3.58 (d, 1H, J=12.7 Hz), 2.98-2.88 (m, 2H),2.55 (d, 2H, J=6.3 Hz), 2.08 (t, 1H, J=11.7 Hz), 1.96-1.81 (m, 2H),1.80-1.69 (m, 2H), 1.59 (qt, 1H, J=4.4, 12.7 Hz), 1.11-0.98 (m, 1H).

EXAMPLE 361(±)-6-[4-(3-Phenyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 345, using 3-phenyl-piperidinehydrochloric acid salt (0.413 g, 2.09 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.500 g, 0.417 mmol), sodium triacetoxyborohydride (0.656 g, 3.10mmol), and acetic acid (0.172 mL, 3.00 mmol) in 1,2-dichloroethane (20.0mL) provides, after reverse-phase HPLC, 0.508 g (64%) of the titlecompound as a white solid: mass spectrum (electrospray): m/z=388.1(M+1); ¹H NMR (DMSO-d₆): 8.65 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.6,8.8 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.39 (d, 2H, J=8.4 Hz),7.35-7.17 (m, 5H), 7.16-7.06 (m, 3H), 3.55 (s, 2H), 2.91 (d, 2H, J=10.6Hz), 2.80 (t, 1H, J=11.3 Hz), 2.05 (q, 2H, J=8.4 Hz), 1.86 (d, 1H,J=11.3 Hz), 1.81-1.56 (m, 2H), 1.48 (dq, 1H, J=4.0, 12.1 Hz).

EXAMPLE 362(±)-6-{4-[3-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamidehydrochloride

Using a method similar to Example 345, using3-(4-fluoro-phenyl)-piperidine (0.117 g, 0.542 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.111 g, 0.458 mmol), sodium triacetoxyborohydride (0.135 g, 0.637mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0mL) provides, after silica gel chromatography (12:1 methylenechloride:methanol) and reverse-phase HPLC, 0.0938 g (51%) of the titlecompound as a white solid: high resolution mass spectrum (electrospray):m/z calc for C₂₄H₂₅FN₃O₂ 406.1931, found 406.1926; ¹H NMR (DMSO-d₆):8.64 (d, 1H, J=2.2 Hz), 8.31 (dd, 1H, J=2.6, 8.8 Hz), 8.08 (s br, 1H),7.68 (d, 2H, J=8.4 Hz), 7.52 (s br, 1H), 7.42-7.08 (m, 5H), 4.33 (s,2H), 3.50-3.30 (m, 2H), 3.30-2.84 (m, 3H), 2.05-1.79 (m, 3H), 1.75-1.57(m, 1H).

EXAMPLE 363(±)-6-{4-[3-(2-Fluoro-phenyl)-piperidin-1-ylmethyl]-phenoxy}-nicotinamidehydrochloride

Using a method similar to Example 345, using3-(4-fluoro-phenyl)-piperidine (0.118 g, 0.547 mmol),6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1)(0.109 g, 0.450 mmol), sodium triacetoxyborohydride (0.132 g, 0.623mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0mL) provides, after silica gel chromatography (12:1 methylenechloride:methanol) and reverse-phase HPLC, 0.0511 g (26%) of the titlecompound as a white solid: high resolution mass spectrum (electrospray):m/z calc for C₂₄H₂₅FN₃O₂ 406.1931, found 406.1933; ¹H NMR (methanol-d₄):8.66 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.68-7.63 (m, 2H),7.45-7.31 (m, 4H), 7.28-7.22 (m, 1H), 7.20-7.14 (m, 2H), 4.47 (d, 1H,J=13.2 Hz), 4.43 (d, 1H, J=13.2 Hz), 3.69-3.59 (m, 2H), 3.52-3.43 (m,1H), 3.27 (t, 1H, J=12.2 Hz), 3.18-3.09 (m, 1H), 2.22-2.15 (m, 1H),2.10-1.87 (m, 3H).

EXAMPLE 364(±)-6-[4-(3-Cyclohexyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamidehydrochloride

Step 1 (±)-3-Cyclohexyl-piperidine

Combine 3-phenyl-piperidine hydrochloride (0.206 g, 1.04 mmol) and 5%rhodium on alumina (0.112 g, 0.0544 mmol) in methanol (50 mL) and stirat 50° C. at a H₂ pressure of 60 psi. After 4 d, purify the reactionmixture by ion exchange chromatography (SCX resin, methanol→2 Mammonia/methanol) to provide 0.164 g (3:1 mixture of product:startingmaterial) which was used in the next step without further purification:mass spectrum (electrospray): m/z=168.1 (M+1−product), 162.1(M+1−starting material).

Step 2

Using a method similar to Example 345, a mixture of3-cyclohexyl-piperidine and 3-phenyl piperidine (from step 1 above)(3:1, 0.118 g), 6-(4-formyl-phenoxy)-nicotinamide (compound of example332, step 1) (0.183 g, 0.755 mmol), sodium triacetoxyborohydride (0.247g, 1.16 mmol), and acetic acid (0.067 mL, 1.17 mmol) in1,2-dichloroethane (10.0 mL) provides, after reverse-phase HPLC, 0.155 g(37%) of the title compound as a white solid: high resolution massspectrum (electrospray): m/z calc for C₂₄H₃₂N₃O₂ 394.2495, found394.2478; ¹H NMR (methanol-d₄): 8.68 (d, 1H, J=2.4 Hz), 8.38 (dd, 1H,J=2.4, 8.3 Hz), 7.69-7.63 (m, 2H), 7.37-7.32 (m, 2H), 7.18 (d, 1H, J=8.8Hz), 4.42 (d, 1H, J=13.2 Hz), 4.34 (d, 1H, J=13.2 Hz), 3.62-3.55 (m,1H), 3.54-3.47 (m, 1H), 2.92 (dt, 1H, J=3.4, 13.2 Hz), 2.84 (t, 1H,J=12.2), 2.08-2.00 (m, 1H), 2.00-1.92 (m, 1H), 1.87-1.66 (m, 7H),1.39-1.02 (m, 7H).

EXAMPLE 365(±)-6-[2-Methyl-4-(3-phenyl-piperidin-1ylmethyl)-phenoxy]-nicotinamide

Step 1 6-(4-Formyl-2-methyl-phenoxy)-nicotinonitrile

Combine 4-hydroxy-3-methyl-benzaldehyde (0.502 g, 3.69 mmol),6-chloro-nicotinonitrile (0.510 g, 3.68 mmol), and potassium carbonate(1.28 g, 9.26 mmol) in dimethylacetamide (18 mL) and warm to 100° C.After 1 h, cool to ambient temperature, dilute reaction mixture withwater (40 mL), and extract with ethyl acetate (3×50 mL). Wash combinedorganic extracts with water and brine successively, dry over anhydrousmagnesium sulfate, filter, and concentrate. Purify the residue by silicagel chromatography (hexanes→ethyl acetate gradient/1.5 L) to provide0.784 g (89%) of the title compound as a light brown solid: massspectrum (electrospray): m/z=239.0 (M+1);

¹H NMR (CDCl₃): 10.01 (s, 1H), 8.44 (d, 1H, J=2.4 Hz), 7.99 (dd, 1H,J=2.0, 8.3 Hz), 7.86 (s, 1H), 7.81 (dd, 1H, J=1.5, 8.3 Hz), 7.23 (d, 1H,J=8.3 Hz), 7.13 (d, 1H, J=8.8 Hz), 2.25 (s, 3H).

Step 2(±)-6-[2-Methyl-4-(3-phenyl-piperidin-1ylmethyl)-phenoxy]-nicotinonitrile

Convert 3-phenyl piperidine hydrochloride (0.652 g, 3.30 mmol) to thefree base using ion exchange chromatography (methanol→2 Mammonia/methanol) and concentrate. Combine the free base with6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (from step 1 above) (0.748g, 3.29 mmol), sodium triacetoxyborohydride (1.05 g, 4.95 mmol), andacetic acid (0.30 mL, 5.24 mmol) in 1,2-dichloroethane (33 mL) and stirat ambient temperature. After 17 h, wash reaction mixture with saturatedsodium bicarbonate (aq) (2×50 mL), dry over anhydrous magnesium sulfate,filter, and concentrate. Purify the residue by silica gel chromatography(hexanes→2:1 hexanes:ethyl acetate) to provide 0.878 g (70%) of thetitle compound as a white foam: ¹H NMR (CDCl₃): 8.46 (d, 1H, J=2.9 Hz),7.91 (dd, 1H, J=2.9, 8.8 Hz), 7.34-7.19 (m, 7H), 6.99 (d, 2H, J=8.8 Hz),3.52 (s, 2H), 3.06-2.94 (m, 2H), 2.86 (tt, 1H, J=3.9, 11.7 Hz), 2.13 (s,3H), 2.10-1.91 (m, 3H), 1.84-1.68 (m, 2H), 1.48 (dq, 1H, J=4.9, 12.2Hz).

Step 3

The nitrile from step 2 may be hydrolyzed to the amide final product asdescribed many times herein.

EXAMPLE 366(±)-6-[2-Methyl-4-(3-phenyl-pyrollidin-1ylmethyl)-phenoxy]-nicotinamide

Step 1(±)-6-[2-Methyl-4-(3-phenyl-pyrollidin-1ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 362, using 3-phenyl-pyrrolidinephosphoric acid salt (1.543 g, 6.29 mmol),6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (compound of example 365,step 1) (1.499 g, 6.30 mmol), sodium triacetoxyborohydride (2.00 g, 9.44mmol), and acetic acid (0.58 mL, 10.1 mmol) in 1,2-dichloroethane (50mL), after silica gel chromatography (19:1→1:3 hexanes:ethyl acetate)provides 1.65 g (71%) of the title compound as a clear syrup: Massspectrum (electrospray): m/z=370.1 (M+1); ¹H NMR (CDCl₃): 8.47 (d, 1H,J=2.4 Hz), 7.91 (dd, 1H, J=2.0, 8.3 Hz), 7.32-7.28 (m, 5H), 7.26-7.17(m, 2H), 3.67 (s, 2H), 3.45-3.35 (m, 1H), 3.08 (t, 1H, J=9.3 Hz).2.93-2.85 (m, 1H), 2.72 (dt, 1H, J=5.9, 8.8 Hz), 2.53 (dd, 1H, J=8.3,9.3 Hz), 2.43-2.32 (m, 1H), 2.14 (s, 3H), 1.99-1.88 (m, 1H).

Step 2

Basic hydrolysis of(±)-6-[2-Methyl-4-(3-phenyl-pyrollidin-1ylmethyl)-phenoxy]-nicotinonitrileas discussed for other nitriles previously is useful to obtain thedesired nicotinamide product.

EXAMPLE 367(±)-6-[2-Methyl-4-(3-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinamide

Step 1(±)-6-[2-Methyl-4-(3-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 365 step 2, using 3-phenyl-azapane(0.0610 g, 0.348 mmol), 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile(compound of example 365 step 1) (0.0816 g, 0.342 mmol), sodiumtriacetoxyborohydride (0.110 g, 0.519 mmol), and acetic acid (0.032 mL,0.56 mmol) in 1,2-dichloroethane (4.0 mL), (no aqueous work-up)provides, after ion exchange chromatography (methanol→2 Mammonia/methanol) and silica gel chromatography (4:1→1:1 hexanes:ethylacetate), 0.0899 g (65%) of the title compound as a yellow oil: Massspectrum (electrospray): m/z=398.2 (M+1).

Step 2

The nitrile from above is hydrolyzed under basic conditions to affordthe target nicotinamide compound.

EXAMPLE 368(±)-6-[2-Methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinamide

Step 1(±)-6-[2-Methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 365 step 2, using 3-phenyl-azapane(0.0957 g, 0.548 mmol), 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile(compound of example 365 step 1) (0.103 g, 0.420 mmol), sodiumtriacetoxyborohydride (0.110 g, 0.651 mmol), and acetic acid (0.034 mL,0.594 mmol) in 1,2-dichloroethane (5.0 mL), provides, after silica gelchromatography (4:1→1:1 hexanes:ethyl acetate), 0.144 g (84%) of thetitle compound as a yellow oil: mass spectrum (electrospray): m/z=398.2(M+1); ¹H NMR (CDCl₃): 8.47 (d, 1H, J=1.5 Hz), 7.91 (dd, 1H, J=1.5, 7.8Hz), 7.33-7.25 (m, 4H), 7.25-7.21 (m, 2H), 7.21-7.15 (m, 1H), 7.03-6.97(m, 2H), 3.73-3.67 (m, 2H), 2.90-2.81 (m, 2H), 2.79-2.66 (m, 3H), 2.15(s, 3H), 2.01-1.67 (m, 6H).

Step 2

The nitrile compound from step 1 is hydrolyzed under basic conditions toafford the corresponding nitrile, as described previously in the generalmethodology sections.

EXAMPLE 369(±)-6-[2-Methyl-4-(3-phenyl-piperidin-1ylmethyl)-phenoxy]-nicotinamidemethanesulfonate

Combine(±)-6-[2-methyl-4-(3-phenyl-piperidinylmethyl)-phenoxy]-nicotinonitrile(compound of example 365, step 2) (0.878 g, 2.29 mmol) and potassiumcarbonate (0.159 g, 1.15 mmol) in dimethylsulfoxide (11.0 mL,). Treatthe mixture with 30% hydrogen peroxide solution (aq) (0.77 mL, 6.79mmol), and stir at ambient temperature. After 4 h, dilute the reactionmixture with water (25 mL) and extract with ethyl acetate (3×30 mL).Wash combined ethyl acetate extracts with brine, dry over anhydrousmagnesium sulfate, filter, and concentrate. Crude product is pure by ¹HNMR and reverse-phase HPLC. Dissolve product in tetrahydrofuran (12 mL)and treat with methanesulfonic acid (0.148 mL, 2.28 mmol). Whiteprecipitate forms and turns oily within 3 minutes. Dissolve residue intetrahydrofuran and concentrate. Product purity is 82% by reverse-phaseHPLC. Purify residue by reverse-phase HPLC. Concentrate fractionscontaining pure product, recrystallize from methanol:diethyl ether (2:5,16 mL), and isolate product by vacuum filtration to provide 0.0941 g(10%) of the title compound as white/tan crystals: high resolution massspectrum (electrospray): m/z calc for C₂₅H₂₈N₃O₂ 402.2182, found402.2172; ¹H NMR (methanol-d₄): 8.62 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H,J=2.4, 8.8 Hz), 7.57-7.54 (m, 1H), 7.48 (dd, 1H, J=1.5, 7.8 Hz),7.43-7.38 (m, 2H), 7.37-7.30 (m, 3H), 7.23 (d, 1H, J=8.3 Hz), 7.16 (d,1H, J=8.8 Hz), 4.45-4.36 (m, 2H), 3.63 (t, 2H, J=14.6 Hz), 3.22 (t, 1H,J=12.2 Hz), 3.17-3.07 (m, 2H), 2.23 (s, 3H), 2.20-2.13 (m, 1H),2.12-2.92 (m, 2H), 1.86 (dq, 1H, J=3.9, 12.2 Hz).

EXAMPLE 370(±)-6-[2-Methyl-4-(3-phenyl-pyrollidin-1yl-methyl)-phenoxy]-nicotinamidehydrochloride

Combine(±)-6-[2-methyl-4-(3-phenyl-pyrollidin-1yl-methyl)-phenoxy]-nicotinonitrile(compound of example 366) (0.642 g, 1.74 mmol) and potassium carbonate(0.125 g, 0.904 mmol) in dimethylsulfoxide (10.0 mL), treat with 30%hydrogen peroxide solution (aq) (0.60 mL, 5.3 mmol), and stir at ambienttemperature. After 5 h, dilute the reaction mixture with water (25 mL)and extract with ethyl acetate (3×25 mL). Wash combined ethyl acetateextracts with brine, dry over anhydrous magnesium sulfate, filter, andconcentrate to provide 0.660 g (98%) of the title compound (free base)as a white solid. Dissolve product in methylene chloride (10 mL) andtreat with 4 N hydrochloric acid/dioxane (0.47 mL, 1.87 mmol). Somedecomposition occurs. Purify product by reverse-phase HPLC to provide0.184 g (25%) of the title compound as a white solid: mass spectrum(electrospray): m/z=388.2 (M+1); ¹H NMR methanol-d₄): 8.63 (d, 1H, J=1.5Hz), 8.35 (dd, 1H, J=2.4, 8.8 Hz), 7.61 (d, 1H, J=8.8 Hz), 7.54 (d, 1H,J=8.8 Hz), 7.41 (t, 4H, J=4.4 Hz), 7.38-7.30 (m, 1H), 7.23 (d, 1H, J=8.3Hz), 7.14 (d, 1H, J=8.8 Hz), 4.59-4.49 (m, 2H), 3.99-3.72 (m, 2H),3.70-3.41 (m, 2H), 3.48 (t, 1H, J=11.7 Hz), 2.66-2.51 (m, 1H), 2.44-2.15(m, 4H).

EXAMPLE 371 (±)-6-[2-Methyl-4-(3-phenyl-azepan-1-ylmethyl)-phenoxy]-nicotinamide hydrochloride

Combine(±)-6-[2-methyl-4-(3-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile(compound of example 367)(0.0876 g, 0.220 mmol) and potassium carbonate(0.0152 g, 0.11 mmol) in dimethylsulfoxide (2.0 mL), treat with 30%hydrogen peroxide solution (aq) (0.075 mL, 0.66 mmol), and stir atambient temperature. After 2.5 h, dilute the reaction mixture with water(10 mL) and extract with ethyl acetate (3×10 mL). Wash combined extractswith brine, dry over anhydrous magnesium sulfate, filter, andconcentrate. Purify the residue by reverse-phase HPLC to provide 0.0191g (19%) of the title compound as a white solid: high resolution massspectrum (electrospray): m/z calc for C₂₆H₃₀N₃O₂ 416.2338, found416.2347; retention time: 3.834 min. The HCl salt of the free base wasprepared by known protocols.

EXAMPLE 372(±)-6-[2-Methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 371,(±)-6-[2-methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile(compound of example 368) (0.246 g, 0.642 mmol), potassium carbonate(0.0429 g, 0.310 mmol), and 30% hydrogen peroxide solution (aq) (0.220mL, 1.94 mmol) in dimethylsulfoxide provide, after ion exchangechromatography (methanol→2 M ammonia/methanol), 0.223 g (87%) of thetitle compound as a white solid: high resolution mass spectrum(electrospray): m/z calc for C₂₅H₂₈N₃O₂ 402.2182, found 402.2172; ¹H NMR(methanol-d₄): 8.67 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz),7.51 (d, 2H, J=8.3 Hz), 7.32-7.22 (m, 4H), 7.20-7.14 (m, 3H), 7.04 (d,1H, J=8.8 Hz), 3.77 (s, 2H), 2.97 (ddd, 1H, J=3.4, 6.3, 13.2 Hz),2.92-2.83 (m, 3H), 2.81-2.72 (m, 1H), 2.04-1.76 (m, 6H).

EXAMPLE 373(±)-6-[2-Fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Step 1 6-(2-Fluoro-4-formyl-phenoxy)-nicotinonitrile

Using a method similar to Example 365, step 1, using4-hydroxy-3-fluoro-benzaldehyde (3.00 g, 21.4 mmol), 6-chloronicotinonitrile (2.98 g, 21.5 mmol), and potassium carbonate (7.40 g,53.5 mmol) in dimethylacetamide (100 mL) after 6 h at 100° C. provides3.77 g (73%) of the title compound as a yellow solid (silica gelchromatography conditions: 19:1→1:4 hexanes:ethyl acetate): massspectrum (electrospray): m/z=243.0 (M+1); ¹H NMR (CDCl₃): 10.00 (d, 1H,J=2.0 Hz), 8.42 (d, 1H, J=1.5 Hz), 8.01 (dd, 1H, J=2.0, 8.3 Hz),7.80-7.72 (m, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.8 Hz).

Step 2(±)-6-[2-Fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 365 step 2, using 3-phenyl-pyrollidine(0.169 g, 1.15 mmol), 6-(4-formyl-2-fluoro-phenoxy)-nicotinonitrile(compound of example 375 step 1), (0.200 g, 0.826 mmol), sodiumtriacetoxyborohydride (0.262 g, 1.24 mmol), and acetic acid (0.071 mL,1.24 mmol) in 1,2-dichloroethane (8.0 mL), after silica gelchromatography (3:1 hexanes:ethyl acetate), provides 0.231 g (75%) ofthe title compound as a clear syrup: mass spectrum (electrospray):m/z=374.2 (M+1); ¹H NMR (CDCl₃): 8.40 (d, 1H, J=2.9 Hz), 7.91 (dd, 1H,J=2.4, 8.3 Hz), 7.30-7.24 (m, 2H), 7.24-7.21 (m, 3H), 7.20-7.09 (m, 3H),7.06 (d, 1H, J=8.8 Hz), 3.70-3.61 (m, 2H), 3.40-3.31 (m, 1H), 3.01 (t,1H, J=8.8 Hz), 2.84-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.53 (dd, 1H,J=7.8, 9.3 Hz), 2.39-2.28 (m, 1H), 1.95-1.84 (m, 1H).

Step 3

Using a method similar to Example 371,(±)-6-[2-fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile(compound of example 375, step 2) (0.225 g, 0.603 mmol), potassiumcarbonate (0.0425 g, 0.308 mmol), and 30% hydrogen peroxide solution(aq) (0.203 mL, 1.79 mmol) in dimethylsulfoxide (6.0 mL) provide 0.197 g(83%) of the title compound as a white solid: high resolution massspectrum (electrospray): m/z calc for C₂₃H₂₃FN₃O₂ 392.1774, found392.1760; ¹H NMR (methanol-d₄): 8.62 (d, 1H, J=2.4 Hz), 8.32 (d, 1H,J=2.9, 8.8 Hz), 7.41-7.25 (m, 7H), 7.25-7.19 (m, 1H), 7.15 (d, 1H, J=8.3Hz), 3.83 (d, 1H, J=13.2 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.51-3.41 (m,1H), 3.18 (d, 1H, J=9.3 Hz), 3.02-2.94 (m, 1H), 2.86 (td, 1H, J=5.9, 8.8Hz), 2.63 (t, 1H, J=8.8 Hz), 2.46-2.35 (m, 1H), 2.05-1.94 (m, 1H).

EXAMPLE 3746-[2-(5-Methylhexyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 1-bromo-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at50° C. overnight, then increase the temperature to 80° C. for 3.5 hours.Cool the reaction mixture to room temperature and add ethyl acetate (100mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layerover Na₂SO₄, filter and concentrate. Purify by flash chromatographyeluting with 6% to 15% (2.0 M NH₃ in methanol) in ethyl acetate to givethe title compound: MS ES⁺ 382.2 (M+H)⁺, HRMS calcd for C₂₃H₃₁N₃O₂382.2492 (M+H)⁺, found 382.2495, time 0.46 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], t_(R)=12.4 min,97.7% purity.

EXAMPLE 3756-(2-Methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Ex 414, Part B) (0.100g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6mL), cap and stir the mixture overnight. Add NaBH₄ (ca. 3-5 eq in twoportions) and stir until the gasses stop evolving. Load the reactionmixture directly onto a 5 g ISCO® pre-load column. Dry the column in avacuum oven at room temperature. Purify by eluting through a 10 g ISCO®column with 6% to 15% (2.0 M NH₃ in methanol) in ethyl acetate to give6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide.Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalentof 0.50 M methanesulfonic acid in dichloromethane. Stir the solution fora short time before concentrating to give the title compound: TOF MS ES⁺398.2 (M+H)⁺, HRMS calcd for C₂₃H₃₂N₃O₃ 398.2444 (M+H)⁺, found 398.2440,time 0.52 min; Anal. Calcd for C₂₃H₃₁N₃O₃.0.5H₂O: C, 57.35; H, 7.22; N,8.36. Found: C, 57.33; H, 6.94; N, 8.34.

EXAMPLE 376(±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Step 1 6-(2-Ethoxy-4-formyl-phenoxy)-nicotinonitrile

Using a method similar to Example 365, step 1, and using3-ethoxy-4-hydroxy-benzaldehyde (3.00 g, 18.0 mmol),6-chloro-nicotinonitrile (2.65 g, 18.0 mmol), and potassium carbonate(6.62 g, 45.2 mmol) in dimethylacetamide (90 mL), after 3 h at 100° C.(no purification) provides 4.52 g (93%) of the title compound as ayellow/white solid: mass spectrum (electrospray): m/z=269.0 (M+1); ¹HNMR (CDCl₃): 9.96 (s, 1H), 8.39 (d, 1H, J=2.0 Hz), 7.95 (dd, 1H, J=2.0,8.3 Hz), 7.55-7.50 (m, 2H), 7.33 (d, 1H, J=7.8 Hz), 7.11 (d, 1H, J=9.3Hz), 4.05 (q, 2H, J=6.8 Hz), 1.16 (t, 3H, J=6.8 Hz).

Step 2(±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 365 step 2, and using3-phenyl-pyrollidine (0.150 g, 1.02 mmol),6-(4-formyl-2-ethoxy-phenoxy)-nicotinonitrile (0.201 g, 0.749 mmol),sodium triacetoxyborohydride (0.237 g, 1.12 mmol), and acetic acid(0.064 mL, 1.12 mmol) in 1,2-dichloroethane (7.5 mL), after silica gelchromatography (1:1 hexanes:ethyl acetate), provides 0.182 g (61%) ofthe title compound as a clear syrup: mass spectrum (electrospray):m/z=400.2 (M+1); ¹H NMR (CDCl₃): 8.41 (d, 1H, J=2.0 Hz), 7.86 (dd, 1H,J=2.4, 9.3 Hz), 7.29-7.26 (m, 4H), 7.20-7.14 (m, 1H), 7.07-7.03 (m, 2H),6.99 (d, 1H, J=7.8 Hz), 6.94 (dd, 1H, J=2.0, 7.8 Hz), 4.01-3.92 (m, 2H),3.69 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.41-3.31 (m, 1H),3.99 (dd, 1H, J=7.8, 8.8 Hz), 2.86-2.78 (m, 1H), 2.77-2.70 (m, 1H), 2.54(dd, 1H, J=7.3, 9.3 Hz), 2.40-2.29 (m, 1H), 1.96-1.85 (m, 1H).

Step 3

Using a method similar to Example 371, and using(±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile(step 2 above), potassium carbonate (approx. 0.5 equivalent), and 30%hydrogen peroxide solution (aq) (approx. 3 mole equivalents) indimethylsulfoxide provides the title compound.

EXAMPLE 377(±)-6-[2-Chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

Step 1

Using a method similar to Example 365, step 1, and using4-hydroxy-3-chloro-benzaldehyde (3.00 g, 19.2 mmol),6-chloro-nicotinonitrile (2.65 g, 19.1 mmol), and potassium carbonate(6.62 g, 47.9 mmol) in dimethylacetamide (95 mL), after 4 h at 100° C.(silica gel chromatography conditions: 19:1 hexanes:ethyl acetate→ethylacetate) and recrystallization from 1:1 hexanes:diethylether, provides2.32 g (47%) of the title compound as a yellow solid: mass spectrum(electrospray): m/z=259.0 (M+1); ¹H NMR (CDCl₃): 10.01 (d, 1H, J=2.0Hz), 8.42 (d, 1H, J=1.5 Hz), 8.07-8.00 (m, 2H), 7.90 (dd, 1H, J=1.5, 7.8Hz), 7.42 (d, 1H, J=8.3 Hz), 7.21 (d, 1H, J=8.8 Hz).

Step 2(±)-6-[2-Chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile

Using a method similar to Example 365, step 2, using3-phenyl-pyrrolidine (0.160 g, 1.09 mmol),6-(4-formyl-2-chloro-phenoxy)-nicotinonitrile (0.250 g, 0.966 mmol),sodium triacetoxyborohydride (0.308 g, 1.45 mmol), and acetic acid(0.090 mL, 1.57 mmol) in 1,2-dichloroethane (10.7 mL), after silica gelchromatography (7:3 hexanes:ethyl acetate), provides 0.202 g (54%) ofthe title compound as a clear syrup: mass spectrum (electrospray):m/z=390.1 (M+1); ¹H NMR (CDCl₃): 8.41 (d, 1H, J=2.4 Hz), 7.92 (dd, 1H,J=2.4, 8.8 Hz), 7.50 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=2.0, 8.3 Hz),7.30-7.26 (m, 4H), 7.21-7.16 (m, 1H), 7.13 (d, 1H, J=8.3 Hz), 7.07 (d,1H, J=8.3 Hz), 3.70-3.62 (m, 2H), 3.42-3.32 (m, 1H), 3.03 (t, 1H, J=8.8Hz), 2.87-2.79 (m, 1H), 2.75-2.68 (m, 1H), 2.54 (t, 1H, J=7.8 Hz),2.40-2.29 (m, 1H), 1.96-1.85 (m, 1H).

Step 3

Using a similar method to Example 371, and using(±)-6-[2-chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile(step 2 above) (0.198 g, 0.508 mmol), potassium carbonate (0.0337 g,0.244 mmol), and 30% hydrogen peroxide solution (aq) (0.180 mL, 1.59mmol) in dimethylsulfoxide (5.0 mL) provides 0.126 g (61%) of the titlecompound as a yellowish syrup: high resolution mass spectrum(electrospray): m/z calc for C₂₃H₂₃ClN₃O₂ 408.1479, found 408.1449; ¹HNMR (methanol-d₄): 8.61 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.4, 8.8 Hz),7.61 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J=2.0, 8.3 Hz), 7.35-7.29 (m, 4H),7.27 (d, 1H, J=8.3 Hz), 7.24-7.18 (m, 1H), 7.11 (d, 1H, J=8.8 Hz), 3.80(d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.2 Hz), 3.50-3.39 (m, 1H), 3.15(dd, 1H, J=7.8, 9.3 Hz), 2.99-2.91 (m, 1H), 2.82 (td, 1H, J=6.3, 8.8Hz), 2.60 (t, 1H, J=8.8 Hz), 2.45-2.34 (m, 1H), 2.03-1.92 (m, 1H).

EXAMPLE 3786-(3-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide

Step 1: N-(2,2-Dimethoxyethyl)-2-(3-methoxyphenyl)-N-methylacetamide

3-methoxyphenylacetyl chloride

Dissolve (methylamino)acetaldehyde dimethyl acetal (365 mL, 2.84 mol,1.05 eq) in saturated aqueous NaHCO₃/CHCl₃ (4 L/5.5 L) at roomtemperature in a 22 L reaction flask. Add 3-methoxyphenacetyl chloride(500 g, 2.71 mol, 1.0 eq) via an addition funnel to the reaction flaskover 30 minutes (added at a rate sufficient to control off-gassing).Stir the biphasic mixture for 3 hours vigorously. The reaction isdetermined to be complete by TLC (hexanes/ethyl acetate). Collect theCHCl₃ layer, and dry over sodium sulfate and purify by a silica plug(elute with 1/1 ethyl acetate/hexanes) to obtainN-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)-N-methylacetamide (productwith solvent). ¹H NMR (CDCl₃): 7.26-7.20 (m, 1H); 6.84-6.77 (m, 3H);4.52 (t, J=5.6 Hz. 0.7H); 4.4.27 (t, J=5.6 Hz, 0.3H); 3.79 (twosinglets, total 3H) 3.77 (s, 0.7H); 3.70 (s, 1.3H);.3.46 (d, J=5.6 Hz,1.3H); 3.39 (d, J=5.6 Hz, 0.7H); 3.38 (two singlets, total 6H); 3.05 (s,2H); 2.99 (s, 1H).

Step 2: 8-Methoxy-3-methyl-1,3-dihydrobenzo[d]azepin-2-one

Add concentrated HCl (3.5 L) to a solution ofN-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)-N-methylacetamide (790 g,2.709 mol, 1.0 eq) dissolved in HOAc (3.5 L). Stir the mixture for 16hours at room temperature. Dilute the reaction mixture with 4 L ofdichloromethane and then quench slowly with 50% NaOH (4.0 L) over 2hours. Separate the two layers. Collect the organic layer, dry oversodium sulfate and concentrate under vacuum to yield an off-white solid.The solid is put through a silica plug (1/1 hexanes/ethyl acetate) toobtain the product (Cmpd N, 460 g, 84% yield).

MS Found: 204.1 (M+H)⁺

Step 3: 8-Methoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one

Weigh out 5% Pd on carbon (100 g) to a suitable container and wet thecatalyst with ethyl acetate (2 L) while maintaining a nitrogen blanket.Charge the catalyst slurry to a 10-gallon autoclave and rinse thecontainer with ethyl acetate (1 L) while maintaining a nitrogen purge.Add 8-methoxy-3-methyl-1,3-dihydrobenzo[d]azepin-2-one (920 g, 4.5 mol)to the autoclave and rinse with ethyl acetate (4 L). Purge the autoclavewith nitrogen, seal the autoclave and pressurize with hydrogen to 50 psiwhile stirring at 800 rpm and maintaining the reaction temperaturebetween 20-30° C. The reaction is determined to be complete by 1H NMRafter 5 hours. Filter the autoclave contents over hyflo and rinse withethyl acetate, then concentrate the filtrate to obtain the productmethoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one as an off-whitesolid (868 g, 93% yield).

MS Found: 206.1 (M+H)⁺

Step 4: 7-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve methoxy-3-methyl-1,3,4.5-tetrahydrobenzo[d]azepin-2-one (375 g,183 mmol, 1.0 eq) in THF (2.5 L) and add the solution via an additionfunnel over 1 hour to slurry of lithium aluminum hydride (LAH) (175 g,457 mmol, 2.5 eq) in ether/THF (4.5 L/2 L) in a 22 L reaction vesselunder nitrogen while cooled in an ice/acetone bath. Add the startingamide at a rate to maintain the reaction temperature below 30° C. Stirthe resulting mixture for 3 hours at room temperature under nitrogen.The reaction is determined to be complete by TLC. Cool the reactionmixture in an ice/acetone bath and quench slowly over 2 hours(off-gassing, exothermic) with water (175 mL) and 5.0 N NaOH solution(350 mL) added in succession. Filter the slurry and wash the solids withTHF. Add sodium sulfate to the filtrate to remove any excess water, andthen filter. Concentrate the filtrate down under vacuum to a dark oil toobtain the productmethoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (360 g,quantitative yield).

MS Found: 192.1 (M+H)⁺

Step 5: 7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride

The reactions are set up in a 22 L flask, each equipped with amechanical stirrer, heating mantle, condenser and nitrogen bubbler. Add1-chloroethyl chloroformate (620 mL, 5.750 mol, 10.0 eq) over 1 hour tomethoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 g, 575 mmol,1.0 eq) dissolved in 1,2-dichloroethane (8.0 L) at 60° C., undernitrogen, in a 22 L flask. The solution turns dark purple over the next2 hours. Heat the mixture to reflux and stir for 16 hours undernitrogen. The reaction is determined to be complete by TLC. Cool thereaction flask and concentrate under vacuum to an oil. Dissolve the oilin methanol (4 L) and add to a 22 L reaction flask and stir for 16 hoursat room temperature under nitrogen. Concentrate the resulting solutionunder vacuum to an off-white solid 220 g, 90% yield).

Step 6:2,2,2-Trifluoro-1-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone

Add trifluoroacetic anhydride (400 mL, 2.780 mol, 1.1 eq) dissolved indichloromethane (500 mL) to a solution ofmethoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (541 g,2.530 mol, 1.0 eq) in dichloromethane (7.5 L) and pyridine (450 mL,5.570 mol, 2.2 eq) at 0° C. Stir the resulting solution for 16 hours atroom temperature under nitrogen. The reaction is determined to becomplete by TLC. Quench the reaction and wash with 6.0 N HCl (2×1 L).Collect the organic layer and purify using a silica plug (1 kg) withDarco® (approximately 100 g) and elute with dichloromethane. Concentratethe eluant to a solid under vacuum. Place the solid in a vacuum oven for16 hours at room temperature to give the title compound (605 g, 88%yield).

GC/MS (m/e): 273 (M)⁺

Step 7:2,2,2-Trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone

Dissolve2,2,2-trifluoro-1-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone(10.0 g, 36.6 mmol) in dichloromethane (750 mL). Add BBr₃ (11.0 mL, 116mmol) and stir for 4 hours. Quench the reaction mixture with water (350mL). Filter the suspension, then separate the two layers. Extract theaqueous layer with dichloromethane (2×300 mL). Dry the combined organicextracts over MgSO₄, filter and concentrate to give the title compound(8.62 g, 91%): MS ES⁺ 260 (M+H)⁺, ES⁻ 258 (M−H)⁻; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 30-99% over 19 min], t_(R)=8.8 min, 100%purity.

Step 8:6-[3-(2,2,2-Trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]nicotinamide

Add2,2,2-trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone(0.750 g, 2.89 mmol), 6-chloronicotinamide (0.377 g, 2.41 mmol) andK₂CO₃ (0.833 g, 6.03 mmol) to a round bottom equipped with a Dean-Starktrap. Add toluene (6 mL) and DMF (18 mL). Heat at reflux for two hours.Cool the reaction mixture to 100° C. and stir overnight. Remove thetoluene and DMF as an azeotrope with xylenes. Suspend the solid in 5%methanol/ethyl acetate (100 mL) and filter. Wash the filter cake withethyl acetate. Concentrate the filtrate, then purify by flashchromatography, eluting with 40% ethyl acetate in dichloromethane togive the title compound (0.312 g, 34.0%): MS ES⁺ 380 (M+H)⁺; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min],t_(R)=8.5 min, 89% purity.

Step 9: 6-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide

Dissolve6-[3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]nicotinamide(0.306 g, 0.806 mmol) in 7.0 M NH₃ in methanol (10 mL). Seal the roundbottom and allow to sit without stirring. After three hours, concentrateto give the title compound (0.22 g, 100%): MS ES⁺ 284.1 (M+H)⁺; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min],t_(R)=1.2 min, 93% purity.

Step 10:6-(3-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide

Take up 6-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide(0.0500 g, 0.176 mmol) and K₂CO₃ (0.0488 g, 0.353 mmol) in DMF (1.0 mL).Add 2-bromoethylbenzene (0.0265 mL, 0.194 mmol) and heat to 70° C.overnight. Remove DMF as an azeotrope with xylenes. Purify by 5 g SCXcolumn by washing with methanol and eluting with 2.0 M NH₃ in methanol.Then purify by flash chromatography, eluting with 0-10% ethyl acetateand 5% (2.0 M NH₃ in methanol) in dichloromethane to give the titlecompound: MS ES⁺ 388.1 (M+H)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 30-99% over 19 min], t_(R)=1.7 min, 100% purity.

EXAMPLE 3796-(3-Benzyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotinamide

Using a method similar to Example 378, part J, using6-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide (Part I)and a slight excess of benzyl bromide affords the title compound (0.0291g, 44.2%): TOF ES⁺ 374.2 (M+H)⁺, HRMS calcd for C₂₃H₂₄N₃O₂ 374.1869(M+H)⁺, found 374.1870, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HClat 1.0 mL/min, 30-99% over 19 min], t_(R)=1.6 min, 100% purity.

EXAMPLE 380 6-[4-(Phenethylaminomethyl)phenoxy]nicotinamidine

Part A: 4-(Phenethylaminomethyl)phenol

Dissolve 4-hydroxybenzaldehyde (1.00 g, 8.12 mmol) in methanol (40.6mL). Add 3 Å molecular sieves and phenethylamine (1.02 mL, 8.12 mmol).Stir at room temperature for 17 hours. Add NaBH₄ (0.341 g, 9.01 mmol).After five hours, filter and concentrate. Purify by 10 g SCX columnwashing with methanol and eluting with 2.0 M NH₃ in methanol to give thetitle compound as an off white solid: HRMS calcd for C₁₅H₁₈NO 228.1388(M+H)⁺, found 228.1387, time 0.74 min, MS TOF ES⁺ 228.1 (M+H)⁺; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min],t_(R)=1.4 min, 100% purity.

Part B: (4-Hydroxybenzyl)phenethylcarbamic acid tert-butyl ester

Suspend 4-(phenethylaminomethyl)phenol (0.750 g, 3.30 mmol) indichloromethane (10 mL). Add a solution of (BOC)₂O (1.08 g, 4.95 mmol)in dichloromethane (6.5 mL). Quench with 1.0 N NaOH (75 mL) after 19hours. Extract with dichloromethane (2×200 mL). Wash the organic layerwith brine (1×75 mL), dry over Na₂SO₄, filter and concentrate. Purify byflash chromatography, eluting with 20-30% ethyl acetate in hexanes togive the title compound (0.570 g, 52.8%): MS ES⁺ 328.3 (M+H)⁺, base peakES⁺ 272.1 (M+2H—C(CH₃)₃)⁺, ES⁻ 326.3 (M−H)⁻; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 30-99% over 19 min], t_(R)=14.7 min,100% purity.

Part C: 6-Chloronicotinamidine

Suspend ammonium chloride (1.16 g, 21.6 mmol) in toluene (10 mL). Coolto 0° C. and slowly add 2.0 M Al(CH₃)₃ in toluene (10.8 mL, 21.6 mmol)(see Tetrahedron Lett. 1990, 31(14), 1969-1972). After the gas stopsevolving, add a solution of 6-chloronicotinonitrile (1.00 g, 7.22 mmol)in toluene (52 mL). Beat to 80° C. overnight. Cool the reaction mixture,then slowly pour into slurry of silica gel (40 g) in CHCl₃ (200 mL).Stir for 10 minutes before filtering. Filter and wash the silica plugwith methanol (2×100 mL). Concentrate the filtrate and purify by 10 gSCX column washing with methanol and then eluting with 2.0 M NH₃ inmethanol to give the title compound (0.458 g. 40.8%): MS ES⁺ 155.9(M+H)⁺: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrilein water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19min], t_(R)=1.2 min, 97.2% purity.

Part D: [(6-Chloropyridin-3-yl)iminomethyl]carbamic acid tert-butylester

Suspend 6-chloronicotinamidine (0.442 g, 2.84 mmol) in THF (28 mL). Adda solution of (BOC)₂O (0.620 g, 5.68 mmol) in THF (4 mL). Concentrateafter 16.5 hours. Purify by flash chromatography, eluting with 10-30%ethyl acetate in dichloromethane to give the title compound (0.685 g,94.3%): MS ES⁺ 256.0 (M+H)⁺, base peak ES⁺ 199.9 (M+2H—C(CH₃)₃)⁺, ES⁻254.1 (M−H)⁻; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min,30-99% over 19 min], t_(R)=1.5 min, 100% purity.

Part E: 6-[4-(Phenethylaminomethyl)phenoxy]nicotinamidine

Take up (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (0.0900g, 0.275 mmol), [(6-chloropyridin-3-yl)iminomethyl]carbamic acidtert-butyl ester (0.0703 g. 0.275 mmol) and K₂CO₃ (0.0950 g, 0.687 mmol)in DMF (2.7 mL). Beat at 60° C. for 3 hours. Then increase thetemperature to 80° C. for an additional 22 hours. Concentrate thereaction mixture. Add ethyl acetate to the resulting solid, stir andfilter. Concentrate the filtrate. Add dichloromethane (0.50 mL) to thesolid, then TFA (0.42 mL). Stir for 3.5 hours at room temperature.Concentrate the reaction mixture. Purify by flash 40 chromatography,eluting with 70% (2.0 M NH₃ in methanol) in ethyl acetate. Load theproduct onto a 5 g SCX column. Wash with methanol and elute with 7.0 MNH₃ in methanol to give the title compound (0.0165 g, 17.3%): MS ES⁺347.0 (M+H)⁺, base peak ES⁺ 243.0 (M+2H—CH₂CH₂C₆H₅)⁺; HPLC [YMC-Pack ProC-18 (150×4.6 mm. S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 30-99% over 19 min], t_(R)=4.7 min, 100%purity.

EXAMPLE 381 6-[4-(2-Benzylaminoethyl)phenoxy]nicotinonamide

Part A [2-(4-Hydroxyphenyl)ethyl]carbamic acid tert-butyl ester

Suspend tyramine (10.0 g, 73.0 mmol) in THF (200 mL). Cool to 0° C. Adda solution of (BOC)₂O (31.8 g, 145 mmol) in THF (43 mL). Allow reactionmixture to warm to room temperature overnight. After 20 hoursconcentrate. Purification through two Waters 500A columns on a PrepLCsystem 500A to give the title compound: MS FAB ES⁺ 238.3 (M+H)⁺, basepeak 182.2 (M+2H—C(CH₃)₃)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 30-99% over 19 min], t_(R)=8.5 min, 100% purity.

Part B 6-[4-(2-Aminoethyl)phenoxy]nicotinonitrile

Take up [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (5.00g, 21.1 mmol), 6-chloronicotinonitrile (2.05 g, 14.8 mmol) and K₂CO₃(5.10 g, 36.9 mmol) in toluene (37 mL) and DMF (111 mL). Beat at refluxfor 1.5 hours. Then cool to 100° C. and stir overnight at 100° C. Removesolvents as an azeotrope with xylenes.

Suspend the solid in dioxane (73.8 mL). Add 4.0 M HCl in dioxane (73.8mL). Stir at room temperature for three days. Filter the precipitate.Wash the filter cake with dioxane (1×30 mL), 50% ether in dioxane (1×30mL) and ether (30 mL). Purify the filter cake using two Waters 500Acolumns on a PrepLC 500A system to give the title compound: HRMS calcdfor C₁₄H₁₄N₃O 240.1137 (M+H)⁺, found=240.1139, time 0.38 min, MS TOF ES⁺240.1 (M+H)⁺, base peak 223.1 (M−NH₂)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HClat 1.0 mL/min, 30-99% over 19 min], t_(R)=1.6 min, 100% purity.

Part C 6-[4-(2-Benzylaminoethyl)phenoxy]nicotinonitrile

Dissolve 6-[4-(2-aminoethyl)phenoxy]nicotinonitrile (2.09 g, 8.75 mmol)in methanol. Add 3 Å molecular sieves and benzaldehyde (0.89 mL, 8.75mmol). Stir at room temperature for 18 hours. Add NaBH₃CN (1.10 g).After the bubbling subsides, filter. Purify by flash chromatography,eluting with 3% (2.0 M NH₃ in methanol) in dichloromethane to give thetitle compound: HRMS calcd for C₂₂H₂₀N₃O 330.1620 (M+H)⁺, found330.1620, time 0.39 min, MS TOF ES⁺ 330.2 (M+H)⁺; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 30-99% over 19 min], t_(R)=2.4 min, 100%purity.

Part D {2-[4-(5-Aminomethylpyridin-2-yloxy)phenyl]ethyl}benzylamine

Dissolve 6-[4-(2-benzylaminoethyl)phenoxy]nicotinonitrile 0.0650 g,0.197 mmol) in THF (2.0 mL). Heat to 65° C. before addingborane-dimethyl sulfide (0.021 mL, 0.217 mmol). Continue heating forabout 2 hours. Then add 5.0 N HCl (0.30 mL). Heat at reflux for 1 hour20 minutes before cooling to room temperature. Add 1.0 N NaOH until thesolution is basic. Extract with ether (3×25 mL). Concentrate the organiclayer before purifying by flash chromatography, eluting with 10% (2.0 MNH₃ in methanol), 10% methanol and 80% ethyl acetate. Load the productonto a 1 g SCX column with methanol. Wash with methanol and elute with2.0 M NH₃ in methanol. Run a second flash 40 column eluting with 10%(2.0 M NH₃ in methanol), 5% methanol and 85% ethyl acetate. Load theproduct onto a 5 g SCX column with methanol. Wash the column withmethanol (4×10 mL) and 25% (2.0 M NH₃ in methanol) in methanol (1×10mL). Then elute with 50% (2.0 M NH₃ in methanol) in methanol to give thetitle compound (0.0141 g, 21.7%): MS ES⁺ 334.0 (M+H)⁺, base peak ES⁺227.0 (M−NHCH₂C₆H₅)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min,30-99% over 19 min], t_(R)=4.8 min, 91.2% purity.

Part E 6-[4-(2-Benzylaminoethyl)phenoxy]nicotinonamide

The amide, may be prepared from the nitrile from step C above byfollowing basic hydrolysis procedures described previously.

EXAMPLE 382 5-[4-(Phenethylaminomethyl)phenoxy]pyridine-2-carboxyamide

Part A: 2-Bromo-5-fluoropyridine

To a 3-neck flask equipped with a dropping funnel and thermometer, add48% HBr (44.4 mL) and cool to <0° C. in an acetone/CO₂ bath. Add2-amino-5-fluoropyridine (10 g, 89.2 mmol) over 12 minutes. With thetemperature <0° C., add Br₂ (13.4 mL, 268 mmol) over 20 minutes. Coolthe reaction mixture to <−10° C. Add a solution of NaNO₂ (15.5 g, 223mmol) in water (50 mL) over 1.5 hours. Stir for additional 30 minutes.Add a solution of NaOH (33.6 g, 838 mmol) in water (50 mL) over 30minutes. Remove the acetone/CO₂ bath and allow the reaction mixture towarm to 5° C. Extract the solution with ether (3×150 mL). Wash theorganic layer with water (1×75 mL) and brine (1×75 mL). Dry the organiclayer over Na₂SO₄, filter and concentrate to give an orange-red solid asthe title compound (14.1 g, 89.8%): TOF MS EI⁺ 176.9 (M+H)⁺, HRMS calcdfor C₅H₃NBrF 174.9433, found 174.9438, time 2.27 min; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 30-99% over 19 min], t_(R)=7.9 min, 100% purity.

Part B: 5-Fluoropyridine-2-carboxamide

Take up 2-bromo-5-fluoropyridine (0.750 g, 4.26 mmol) and CuCN (0.954 g,10.7 mmol) in DMF (10.7 mL). Heat to reflux for 5 hours. Cool thereaction mixture to 100° C. Add a solution of FeCl₃6H₂O (0.654 g) in 10%HCl solution (30 mL) and stir for 15.5 hours. Cool the reaction mixtureto 80° C. and filter. Add 1.0 N NaOH until the reaction mixture becomesbasic and extract with dichloromethane (3×200 mL). Wash the organiclayer with brine (1×75 mL), dry over Na₂SO₄, filter and concentrate togive the title compound (0.186 g, 31.2%): TOF MS EI⁺ 140.0 (M)⁺, basepeak EI⁺ 97.0 (M−CONH)⁺, HRMS calcd for C₆H₅N₂OF 140.0386, found140.0378, time 3.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 30-99% over 19 min], t_(R)=7.5 min, 100% purity.

Part C: [4-(6-Carbamoylpyridin-3-yloxy)benzyl]phenethylcarbamic acidtert-butyl ester

Dissolve (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester(0.0915 g, 0.279 mol) in DMF (0.090 mL). Add NaH (80% in mineral oil)(0.0092 g, 0.307 mmol). Stir for 30 minutes before adding5-fluoropyridine-2-carboxamide (0.0391 g, 0.279 mmol). Heat at 80° C.for 3 days. Load the reaction mixture directly onto a flash 40 columnand elute with 35% ethyl acetate, 3% 2.0 M NH₃ in methanol and 62%hexanes to give the title compound (0.103 g, 82.4%): MS ES⁺ 448.5(M+H)⁺, base peak ES⁺ 392.3 (M+2H—C(CH₃)₃); HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 5-95% over 19 min, 95% over 19.01-25min], t_(R)=19.5 min, 100% purity.

Part D: 5-[4-(Phenethylaminomethyl)phenoxy]pyridine-2-carboxyamide

Dissolve [4-(6-carbamoylpyridin-3-yloxy)benzyl]phenethylcarbamic acidtert-butyl ester (0.0979 g, 0.219 mmol) in dichloromethane (2.2 mL).Then add TFA (2.2 mL). Stir at room temperature for 5 hours. Load thereaction mixture directly onto an SCX column. Wash with methanol and 33%(2.0 M NH₃ in methanol) in methanol. Elute with 66% (2.0 M NH₃ inmethanol) in methanol to give the title compound (0.744 g, 97.9%): TOFMS ES⁺ 348.2 (M+H)⁺, base peak ES⁺ 227.1 (M−NHCH₂CH₂C₆H₅)⁺, HRMS calcdfor C₂₁H₂₂N₃O₂ 348.1712 (M+H)⁺, found 348.1700, time 0.33 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min],t_(R)=9.0 min, 100% purity.

EXAMPLE 383 2-[4-(2-Benzylaminoethyl)phenoxy]nicotinamide

Part A: {2-[4-(3-Carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester

Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester(Example 377, Part A) (0.500 g, 2.11 mmol) in DMF (10.5 mL). Add NaH(80% in mineral oil) (0.070 g, 2.32 mmol). Stir at room temperature for30 minutes. Add 2-chloronicotinamide (0.330 g, 2.11 mmol) and heat to100° C. Remove DMF as an azeotrope with xylenes after 18¾ hours. Takethe solid up with ethyl acetate (150 mL) and 1.0 N NaOH (75 mL).Separate the two layers. Extract the aqueous layer with ethyl acetate(1×150 mL). Wash the combined organic layers with brine (1×50 mL), dryover Na₂SO₄, filter and concentrate. Purify by flash chromatography,eluting with 35-45% ethyl acetate in dichloromethane to give the titlecompound (0.538 g, 71.4%): MS ES⁺ 358.3 (M+H)⁺, base peak ES⁺ 302.1(M+2H—C(CH₃)₃)⁺, MS ES⁻ 356.4 (M−H)⁻; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HClat 1.0 mL/min, 50-99% over 19 min], t_(R)=12.9 min, 100% purity.

Part B: 2-[4-(2-Aminoethyl)phenoxy]nicotinamide

Dissolve {2-[4-(3-carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester (0.518 g, 1.45 mmol) in dichloromethane (8.4 mL). AddTFA (8.4 mL) and stir at room temperature for 4 hours. Concentrate thereaction mixture. Load the product onto an SCX column with methanol.Wash the column with methanol then elute with 50% (2.0 M NH₃ inmethanol) in methanol to give the title compound (0.38 g, 100%): TOF MSES⁺ 258.1 (M+H)⁺, base peak TOF ES⁺ 241.1 (M−NH₂)⁺, HRMS calcd forC₁₄H₁₆N₃O₂ 258.1243 (M+H)⁺, found 258.1228, time 0.34 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min],t_(R)=13.4 min, 100% purity.

Part C: 2-[4-(2-Benzylaminoethyl)phenoxy]nicotinamide

Take up 2-[4-(2-aminoethyl)phenoxy]nicotinamide (0.0555 g, 0.216 mmol)in methanol (2.1 mL). Add benzaldehyde (0.022 mL, 0.216 mmol) and 3 Åmolecular sieves. Stir at room temperature overnight. Add NaBH₄ (0.0082g, 0.216 mmol) and stir for 6 hours before loading directly onto an SCXcolumn. Wash the column with methanol then elute with 2.0 M NH₃ inmethanol. Purify by flash chromatography, eluting with 4% (2.0 M NH₃ inmethanol) in dichloromethane to give the title compound (0.831 g, 79%):TOF MS ES+ 348.2 (M+H)⁺, HRMS calcd for C₂₁H₂₂N₃O₂ 348.1712 (M+H)⁺,found 348.1721, time 0.35 min; TLC [silica gel 60 F₂₅₄, 5% (2.0 M NH₃ inmethanol) in dichloromethane] R_(f)=0.20.

EXAMPLE 384 6-[4-(2-Benzylainoethyl)phenoxy]pyridine-2-carboxamide

Part A: 6-Bromopyridine-2-carbonitrile

Take up 2,6-dibromopyridine (0.500 g, 2.11 mmol) and CuCN (0.189 g, 2.11mmol) in DMF (5.3 mL). Heat at 100° C. for 22 hours. Cool to roomtemperature. Add water (50 mL) and extract with ethyl acetate (3×100mL). Wash the organic layer with brine (1×75 mL), dry over Na₂SO₄,filter and concentrate. Purify by flash chromatography, eluting with15-40% ethyl acetate in hexanes to give the title compound (0.108 g,30.0%): GC/MS, MS ES⁺ 182 (M−H)⁺, time 8.78 min, % of total 100%; TLC[silica gel 60 F₂₅₄, 30% ethyl acetate in hexanes] R_(f)=0.29.

Part B: {2-[4-(6-Cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester

Using a method similar to Example 381 Part A, using[2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.140 g, 0.588mmol), NaH (80% in mineral oil) (0.194 g. 0.647 mmol) and6-bromopyridine-2-carbonitrile (0.107 g, 0.588 mmol) gives the titlecompound (0.0895 g, 44.8%): MS ES⁺ 340.2 (M+H)⁺, base peak MS ES⁺ 284.0(M+2H—C(CH₃)₃)⁺, MS ES⁻ 338.3 (M−H)⁻; TLC [silica gel 60 F₂₅₄, 40% ethylacetate in hexanes] R_(f)=0.24.

Part C: {2-[4-(6-Carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester

Dissolve {2-[4-(6-cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester (0.814 g, 0.240 mmol) in DMSO (4.8 mL). Add K₂CO₃(0.166 g, 0.120 mmol) and then 30% H₂O₂ (0.071 mL, 0.624 mmol). Stir atroom temperature for 3 hours. Quench the reaction mixture with water (30mL). Extract with ethyl acetate (1×60 mL). Wash the organic layer withwater (1×30 mL), dry over MgSO₄, filter and concentrate to give thetitle compound (68.1 g, 79.5%): MS ES⁺ 357.9 (M+H)⁺, base peak ES⁺ 301.9(M+2H—C(CH₃)₃), MS ES⁻ 356.1 (M−H)⁻; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HClat 1.0 mL/min, 30-99% over 19 min], t_(R)=18.5 min, 94.5% purity.

Part D: 6-[4-(2-Aminoethyl)phenoxy]pyridine-2-carboxyamide

Using a method similar to Example 383 Part B, using{2-[4-(6-carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butylester (0.0631 g, 0.176 mmol) gives the title compound (0.055 g crude):TLC [silica gel 60 F₂₅₄, 10% (2.0 M NH3 in methanol) in dichloromethane]R_(f)=0.13; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min,30-99% over 19 min], t_(R)=4.8 min, 100% purity.

Part E: 6-[4-(2-Benzylaminoethyl)phenoxy]pyridine-2-carboxamide

Dissolve 6-[4-(2-aminoethyl)phenoxy]pyridine-2-carboxamide (0.0452 g,0.176 mmol) in methanol (2.9 mL). Add benzaldehlyde (0.018 mL) and 3 Åmolecular sieves. Stir at room temperature overnight. Add NaBH₄ (0.0066g, 0.176 mmol). Stir for additional 6.5 hours before filtering andconcentrating. Purify by reverse phase chromatography, eluting with0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the titlecompound (9.4 mg, 15.4%): MS ES⁺ 347.9 (M+H)⁺; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01%concentrated HCl at 1.0 mL/min, 5-95% over 19 min], t_(R)=7.6 min, 100%purity.

EXAMPLE 385 2-[4-(2-Benzylaminoethyl)phenoxy]isonicotinamide

Part A: {2-[4-(4-Cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acidtert-butyl ester

Using a method similar to Example 381, Part A, using2-chloroisonicotinonitrile (0.500 g, 3.61 mmol) and[2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377,Part A) (0.856 g, 3.61 mmol) gives the title compound (0.947, 77.6%): MSES⁺ 340.2 (M+H)⁺, base peak MS ES⁺ 284.0 (M+2H—C(CH₃)₃))⁺; TLC [silicagel 60 F₂₅₄, 40% ethyl acetate in hexanes] R_(f)=0.30.

Part B: 2-[4-(2-Aminoethyl)phenoxy]isonicotinonitrile

Using a method similar to Example 382, Part D, using{2-[4-(4-cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butylester (0.200 g, 0.589 mmol) gives the title compound (0.14 g, 100%): TLC[silica gel 60 F₂₅₄, 8% (2.0 M NH₃ in methanol) in dichloromethane]R_(f)=0.32.

Part C: 2-[4-(2-Benzylaminoethyl)phenoxy]isonicotinamide

Dissolve 2-[4-(2-aminoethyl)phenoxy]isonicotinonitrile (0.143 g, 0.589mmol) in methanol (6.0 mL). Add 3 Å molecular sieves and benzaldehyde(0.061 g, 0.598 mmol). Stir at room temperature overnight before addingNaBH₄ (0.0226 g, 0.598 mmol). Quench with 1.0 N NaOH (0.5 mL) thenconcentrate. Purify with a flash 40 column eluting with 5% (2.0 M NH₃ inmethanol), 35% ethyl acetate and 60% dichloromethane.

Dissolve the product in DMSO (12 mL). Add K₂CO₃ (0.041 g, 0.299 mmol),then 30% H₂O₂ (0.18 mL, 1.55 mmol). Stir at room temperature for 1 day.Then heat at 50° C. for 6.5 hours. Allow the reaction mixture to cooldown to room temperature overnight. Quench the reaction with 1.0 N NaOH(30 mL). Extract with dichloromethane (1×75 mL), wash the organic layerwith brine: 1.0 N NaOH (2:1) (1×30 mL), filter and concentrate. Purifyby reverse phase chromatography, eluting with 30-100% 0.1%TFA/acetonitrile in 0.1% TFA/water. Load the product onto an SCX column.Wash with methanol and elute with 2.0 M NH₃ in methanol to give thetitle compound (6.4 mg, 6.1%): MS ES⁺ 347.9 (M+H)⁺, MS ES⁻ 346.2 (M−H)⁻;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=8.3 min,92.2% purity.

EXAMPLE 386 N-Methyl-{6-[4-(phenethylaminomethyl)phenoxy]nicotinamidine

Part A: N-Methyl-6-chloronicotinamidine

Using a method similar to Example 380, Part D, using2-chloronicotinonitrile (1.00 g, 7.32 mmol), 2.0 M Al(CH₃)₃ in toluene(11 mL, 22.0 mmol) and methylamine hydrochloride (1.48 g, 22.0 mmol)gives the title compound (0.952 g, 76.7%): MS ES⁺ 171.8 (M+H)⁺, MS ES⁻168.0 (M−H)⁻; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min],t_(R)=5.0 min, 97.0% purity.

Part B: N-Methyl-6-[4-phenethylaminomethyl)phenoxy]nicotinamidine

Take up N-methyl-6-chloronicotinamidine (0.0552 g, 0.326 mmol),(4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (Example 380,Part B) (0.107 g, 0.326 mmol) and K₂CO₃ (0.225 g, 1.63 mmol) in DMF (1.6mL). Heat at 120° C. for 2.5 hours. Then increase the temperature to140° C. for additional 20 hours. Remove DMF as an azeotrope withxylenes. Take the solid up in dichloromethane:ethyl acetate:methanol(3:5:1) and filter. Load onto an SCX column with methanol. Wash withmethanol and elute with 2.0 M NH₃ in methanol. Concentrate the eluant toyield the N-BOC protected product.

Dissolve the product in dichloromethane (5.0 mL). Add TFA (5 mL) andstir at room temperature for 6 hours. Concentrate the reaction mixture.Load the product onto an SCX column. Wash with methanol, 33% (2.0 M NH₃in methanol) in methanol and 66% (2.0 M NH₃ in methanol) in methanol.Elute with 2.0 M NH₃ in methanol to give the title compound (0.0587 g,50.2%): TOF MS ES⁺ 361.2 (M+H)⁺, HRMS calcd for C₂₂H₂₅N₄O 361.2028(M+H)⁺, found 361.2048, time 0.47 min; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 19 min], t_(R)=8.1 min, 100% purity; Anal. Calcd forC₂₂H₂₄Cl₂N₄O.0.9H₂O: C, 70.15; H, 6.90; N, 14.88. Found: C, 70.03; H,6.71; N, 14.91.

Example 387 5-[4-(Phenethylaminomethyl)phenoxy]pyrazine-2-carboxamide

Part A: 5-Chloropyrazine-2-carboxamide

Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Coolto 0° C. and slowly add 2.0 M Al(CH₃)₃ in toluene (4.3 mL, 8.69 mmol).After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acidmethyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool thereaction mixture to room temperature, then slowly pour into a slurry ofsilica gel (10 g) in CHCl₃ (50 mL). Stir for 10 minutes beforefiltering. Wash the silica plug with methanol (2×100 mL) beforeconcentrating. Take the resulting solid up in dichloromethane and washwith water (30 mL) and brine (40 mL). Dry the organic layer over Na₂SO₄,filter and concentrate. Purify by flash chromatographly, eluting with50% ethyl acetate in hexanes to give the title compound (0.155 g,34.0%): TOF MS EI⁺ 157.0 (M⁺), HRMS calcd for C₅H₄N₃OCl 157.0043 (M+H)⁺,found 157.0047, time 4.19 min HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=7.1 min, 100% purity.

Part B: [4-(5-Carbamoylpyrazin-2-yloxy)benzyl]phenethylcarbamic acidtert-butyl ester

Take up 5-chloropyrazine-2-carboxamide (0.0527 g, 0.334 mmol),(4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (Example 380,Part B) (0.110 g, 0.334 mmol) and K₂CO₃ (0.116 g, 0.836 mmol) in DMF(0.80 mL). Heat at 140° C. for 21.5 hours. Concentrate the reactionmixture then purify by flash chromatography, eluting with 50% ethylacetate in hexanes to give the title compound (0.019 g, 12.7%): MS ES⁺448.8 (M+H)⁺, base peak MS ES⁺ 392.8 (M−C(CH₃)₃)⁺; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 30-99% over 19 min], t_(R)=14.8 min, 100% purity.

Part C: 5-[4-(Phenethylaminomethyl)phenoxy]pyrazine-2-carboxamide

Dissolve [4-(5-carbamoylpyrazin-2-yloxy)benzyl]phenethylcarbamic acidtert-butyl ester (0.015 g, 0.0334 mmol) in dichloromethane (1 mL). AddTFA (1 mL). Stir at room temperature for 6 hours. Load directly onto anSCX (5 g) column. Wash the column with methanol, then elute with 2.0 MNH₃ in methanol to give the title compound (11.5 mg, 98%): MS ES⁺ 348.9(M+H)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min],t_(R)=9.4 min, 98.4 purity.

EXAMPLE 3885-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide

Part A: Ethyl 5-fluoropyridine-2-carboxylate

To a Parr shaker add 2-bromo-5-fluoropyridine (Example 382, Part A)(7.00 g, 39.8 mmol), NaOAc (13.1 g, 159 mmol), absolute ethanol (100 mL)and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II):dichloromethane(1.62 g, 1.99 mmol). Charge the reaction vessel with 50 psi of CO. Heatat 90° C. for 18.25 hours. Cool the reaction mixture before filteringthrough a Celite® pad. Wash the pad with ethyl acetate, then concentratethe filtrate. Purify by flash chromatography, eluting with 25% ethylacetate in hexanes to give the title compound (4.62 g, 68.6%): MS ES⁺169.9 (M+H)⁺, base peak MS ES⁺ 141.8 (M+H—CH₂CH₃)⁺; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 5-95% over 19 min], t_(R)=10.3 min, 97.0 purity.

Part B: 5-Fluoropyridine-2-carboxylic acid

Dissolve ethyl 5-fluoropyridine-2-carboxylate (4.60 g, 27.2 mmol) in THF(34 mL) and methanol (34 mL). Add 1.0 N NaOH (32.6, 32.6 mmol) and stirat room temperature for 1.3 hours. Concentrate the reaction mixture.Then add 1.0 N HCl (32.6 mL), stir and concentrate. Take the solid up in20% methanol, 3% AcOH and 77% dichloromethane and filter through asilica plus. Wash the plug with the solvent listed above until all ofthe product elutes off to give the title compound (3.8 g, 100%): MS ES⁺142.03 (M+H)⁺, HRMS calcd for C₆H₅NO₂F 142.0304 (M+H)⁺, found 142.0306,time 0.46 min, 0.51; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19min], t_(R)=6.3 min, 100% purity.

Part C1: 5-Fluoropyridine-2-carboxamide

Take up 5-Fluoropyridine-2-carboxylic acid (3.82 g, 27.1 mmol) in THF(67.7 mL). Add N-hydroxysuccinimide (3.43 g, 29.8 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.71 g,29.8 mmol). Add DMF (15 mL) to dissolve the gum formed. Stir for 3 hoursat room temperature before adding ammonium chloride (2.17 g, 40.6 mmol).Bubble in ammonia gas for five minutes. Seal the reaction vessel andstir the reaction mixture overnight before concentrating. Take the solidup in water (150 mL) and extract with ethyl acetate (4×225 mL). Dry theorganic layer over Na₂SO₄, filter and concentrate. Purify by flashchromatography, eluting with 25% ethyl acetate, 1% (2.0 M NH₃ inmethanol) and 74% dichloromethane to give the title compound (3.06 g,80.7%): TOF MS EI⁺ 140.0 (M)⁺, TOF MS EI⁺ 97.0 (M+B—CONH₂), HRMS calcdfor C₆H₅N₂OF 140.0386, found 140.0394, time 3.4 min; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 5-95% over 19 min], t_(R)=7.1 min, 100% purity.

Part C2: 4-[1,3]Dioxolan-2-yl-phenol

Mix 4-hydroxybenzaldehyde (1.23 g, 10.1 mmol), imidazole (1.37 g, 20.2mmol), and triisopropylsilyl chloride (2.60 mL, 12.1 mmol) in DMF (10mL) and stir at room temperature for 2 hours. Quench the reaction withsaturated aqueous NH₄Cl (50 mL) and extract with EtOAc (3×100 mL). Washthe organic layers with H₂O and brine (50 mL each). Combine the organiclayers, dry over MgSO₄, concentrate and purify by flash chromatography,eluting with 2.5% Et₂O/hexanes to afford4-triisopropylsilyloxybenzaldehyde (2.78 g, 99%).

Heat at reflux a mixture of the aldehyde (2.1033 g, 7.55 mmol),p-TsOH.H₂O (14.4 mg, 0.076 mmol), and ethylene glycol (4.2 mL, 75.5mmol) in benzene (75 mL) overnight, while removing azeotropically theH₂O formed. Cool and wash with 10% K₂CO₃ (2×50 mL) and brine whichcontains 10% K₂CO₃ (50 mL). Back-extract the aqueous layers with benzeneand Et₂O (100 mL each). Concentrate the combined organic layers afterdrying over Na₂SO₄ to afford(4-[1,3]dioxolan-2-yl-phenoxy)triisopropylsilane.

Dissolve the silyl ether in THF (70 mL) and treat with 1.0 Mtetrabutylammonium fluoride (TBAF) in THF (8.0 mL) at room temperaturefor 1 hour. Concentrate, dissolve the residue in Et₂O (100 mL) and washwith H₂O (2×50 mL) and brine (50 mL). Back-extract the aqueous layerswith Et₂O (2×100 mL). Combine the organic layers, dry over MgSO₄,concentrate and purify by flash chromatography, eluting with 20-30%EtOAc/hexanes to afford the title compound (0.9799 g, 78%): HRMS calcdfor C₉H₁₀O₃ 166.0630 (M)⁺, found 166.0648, time 4.69 min; IR (cm⁻¹) 3278(OH); Anal. Calcd for C₉H₁₀O₃.0.6H₂O: C, 61.08; H, 6.38. Found: C,61.21; H, 6.58.

Following 2-substituted-4-[1,3]dioxolan-2-yl-phenols were prepared in asimilar manner:

2-Chloro-4-[1,3]dioxolan-2-yl-phenol: HRMS EI⁺ calcd for C₉H₉O₃Cl 156.00(M−C₂H₄O)⁺, found 156.00, time 4.69 min.

4-[1,3]Dioxolan-2-yl-2-fluorophenol: HRMS calcd for C₉H₉O₃F 184.0536(M)⁺, found 184.0525, time 4.24 min; IR (cm⁻¹) 3573 (OH).

4-[1,3]Dioxolan-2-yl-2-methoxyphenol: HRMS calcd for C₁₀H₁₂O₄ 196.0736(M)⁺, found 196.0727, time 5.02 min, IR (cm⁻¹) 3497 (OH)

4-[1,3]Dioxolan-2-yl-2-methylphenol: HRMS calcd for C₁₀H₁₂O₃ 180.0786(M)⁺, found 180.0785, time 4.97 min; IR (cm⁻¹) 3409 (OH)

4-[1,3)Dioxolan-2-yl-2-ethoxyphenol: HRMS calcd for C₁₁H₁₄O₄ 210.0892(M)⁺, found 210.0886, time 5.20 min; IR (cm⁻¹) 3400 (OH).

Part D: 5-(4-Formylphenoxy)pyridine-2-carboxamide

Dissolve 4-[1,3]dioxolan-2-ylphenol (Part C2, 0.471 g, 2.85 mmol) in DMF(89.5 mL). Add NaH (80% in mineral oil) (0.128 g, 4.28 mmol). Stir atroom temperature for about an hour before adding5-fluoropyridine-2-carboxamide (0.400 g, 2.85 mmol). Heat at 80° C. for4.5 hours before concentrating to dryness to form5-(4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide.

Take up the acetal product in 88% formic acid (9.5 mL). Stir at roomtemperature for about 3 hours before concentrating. Purify by flashchromatography, eluting with 35% ethyl acetate in dichloromethane togive the title compound (0.744 g): MS ES⁺ 242.8 (M+H)⁺; HPLC [YMC-PackPro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=11.0 min, 89.1%purity.

Part E:5-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide

Suspend 5-(4-formylphenoxy)pyridine-2-carboxamide (0.0271 g, 0.112 mmol)in methanol (2.1 mL). Add 4-fluorophenethylamine (0.015 mL, 0.112 mmol)and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH₄(in small excess) and stir for additional 3 hours. Load the reactionmixture directly onto a 5 g SCX column. Wash the column with methanoland elute with 2.0 M NH₃ in methanol. Purify by flash chromatography,eluting with 70% ethyl acetate, 5% (2.0 M NH₃ in methanol) and 25%hexanes to give the title compound (0.0370 g, 90.5%): TOF MS ES⁺ 366.2(M+H)⁺, base peak TOF MS ES⁺ 227.1 (M−NHCH₂CH₂C₆H₄F)⁺, HRMS calcd forC₂₁H₂₁N₃O₂F 366.1618 (M+H)⁺, found 366.1621, time 0.42 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=10.2 min, 100%purity.

EXAMPLE 3895-{4-[(3-Methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Suspend 5-(4-formylphenoxy)pyridine-2-carboxamide (0.0429 g, 0.160 mmol)in methanol (1.5 mL). Add isoamylamnine (0.0185 mL, 0.112 mmol) and 3 Åmolecular sieves. Stir at room temperature overnight. Add NaBH₄ (insmall excess) and stir for additional 3 hours before filtering. Addsaturated aqueous NaHCO₃ (20 mL) to the filtrate. Extract withdichloromethane (3×50 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify by flash chromatography, eluting with 5% (2.0 M NH₃in methanol), 70% ethyl acetate and 25% hexanes to give the titlecompound as a free base (0.0323 g). Redissolve the product in THF (1 mL)and add a solution of 1.27 M methanesulfonate in THF (0.0298 mL) to givethe title compound (0.039 g, 64.6%): MS ES⁺ 314.0 (M+H)⁺, base peak MSES⁺ 226.9 (M−NHCH₂CH₂CH(CH₃)₂)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm,S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 19 min], t_(R)=9.3 min, 96.0% purity.

EXAMPLE 3905-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Part A: 5-(4-Formyl-2-methylphenoxy)pyridine-2-carboxamide

Using a method similar to Example 388 Part D, using5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol)and 4-[1,3]dioxolan-2-yl-2-methylphenol (Example 388, Part C2) (0.514 g,2.85 mmol) gives the title compound (0.259 g): TLC [silica gel 60 F₂₅₄,30% ethyl acetate in dichloromethane] R_(f)=0.20; HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 5-95% over 19 min], t_(R)=12.1 min, 73.1% purity.

Part B:5-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(4-formyl-2-methylpbenoxy)pyridine-2-carboxamide (0.0429 g, 0.160mmol) and isoamylamine (0.018 mL, 0.160 mmol) gives the title compound(0.0576 g, 92.1%): TOF MS ES⁺ 328.2 (M+H)⁺, base peak MS ES⁺ 241.1(M−NHCH₂CH₂CH(CH₃)₂)⁺, HRMS calcd for C₁₉H₂₆N₃O₂ 328.2025 (M+H)⁺, found328.2015, time 0.33 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=9.9 min, 100% purity.

EXAMPLE 3915-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Part A: 5-(4-Formyl-2-methoxyphenoxy)pyridine-2-carboxamide

Using a method similar to Example 388 Part D, using5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol)and 4-[1,3]dioxolan-2-yl-2-methoxyphenol (Example 386, Part C2) (0.560g, 2.85 mmol) gives the title compound (0.126 g, 16%): MS ES⁺ 272.9(M+H)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 min, S-5 microm). 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min],t_(R)=11.1 min. 97.2% purity.

Part B:5-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (0.043 g, 0.160mmol) and isoamylamine (0.018 mL.0.160 mmol) gives the title compound(0.055 g, 81.2%): TOF MS ES⁺ 344.2 (M+H)⁺, base peak MS ES⁺ 257.1(M−NHCH₂CH₂CH(CH₃)₂)⁺, HRMS calcd for C₁₉H₂₆N₃O₃ 344.1974 (M+H)⁺, found344.1978, time 0.35 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=9.5 min, 97.0% purity.

EXAMPLE 3925-(4-{[2-(3-Trifluoromethylphenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0337g, 0.139 mmol) and 2-(3-trifluoromethylphenyl)ethylamine (0.0263 g,0.139 mmol) gives the title compound (0.0127 g, 18%): MS ES⁺ 415.9(M+H)⁺, base peak MS ES⁺ 226.9 (M−NHCH₂CH₂CH(C₆H₄)CF₃)⁺: HPLC [YMC-PackPro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=11.4 min, 100%purity.

Example 3935-{4-[(2-Thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using 5(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.033 g,0.136 mmol) and 2-(2-thienyl)ethylamine (0.0208 g, 0.163 mmol) gives thetitle compound (0.039 g, 64%): TOF MS ES⁺ 354.1 (M+H)⁺, base peak MS ES⁺227.1 (M−NHCH₂CH₂(C₄H₃S))⁺, HRMS calcd for C₁₉H₂₀N₃O₂S 354.1276 (M+H)⁺,found 354.1298, time 0.30 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=9.5 min, 98.4% purity.

EXAMPLE 3945-{2-Methyl-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formyl-2-methylphenoxy)pyridine-2-carboxamide (Example 390, Part A)(0.0349 g, 0.136 mmol) and 2-(2-thienyl)ethylamine (0.021 mL, 0.163mmol) gives the title compound (0.0462 g, 73%): TOF MS ES⁺ 368.1 (M+H)⁺,base peak MS ES⁺ 241.1 (M−NHCH₂CH₂(C₄H₃S)⁺, HRMS calcd for C₂₀H₂₂N₃O₂S368.1433 (M+H)⁺, found 368.1436, time 0.36 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 5-95% over 19 min], t_(R)=10.0 min, 100% purity.

EXAMPLE 3955-{2-Methoxy-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (Example 391, PartA) (0.0370 g, 0.136 mmol) and 2-(2-thienyl)ethylamine (0.021 mL, 0.163mmol) gives the title compound (0.025 g, 38%): TOF MS ES⁺ 384.1 (M+H)⁺,base peak MS ES⁺ 257.1 (M−NHCH₂CH₂(C₄H₃S)⁺, HRMS calcd for C₂₀H₂₂N₃O₃S384.1382 (M+H)⁺, found 384.1373, time 0.37 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 5-95% over 19 min], t_(R)=9.6 min, 100% purity.

EXAMPLE 3965-{4-[(2-Cyclopentylethylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, and using5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.033g, 0.138 mmol) and 2-cyclopentylethylamine (0.0156 g, 0.138 mmol) givesthe title compound (0:0308 g, 51%): TOF MS ES⁺ 340.2 (M+H)⁺, base peakMS ES⁺ 227.1 (M−NHCH₂CH₂(C₅H₉))⁺, HRMS calcd for C₂₀H₂₆N₃O₂ 340.2025(M+H)⁺, found 340.2039, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,20-99% over 23 min], t_(R)=7.8 min, 95.9% purity.

EXAMPLE 3975-{4-[(2-Cyclopentylethylamino)methyl]-2-methylphenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formyl-2-methylphenoxy)pyridine-2-carboxamide (Example 390, Part A)(0.0353 g, 0.138 mmol) and 2-cyclopentylethylamine (0.0156 g, 0.138mmol) gives the title compound (0.0349 g. 56.3%): TOF MS ES⁺ 354.2(M+H)⁺, base peak MS ES⁺ 241.1 (M−NHCH₂CH₂(C₅H₉))⁺, HRMS calcd forC₂₁H₂₈N₃O₂ 354.2182 (M+H)⁺, found 354.2188, time 0.38 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=8.5 min, 96.0%purity.

EXAMPLE 3985-{4-[(2-Cyclopentylethylamino)methyl]-2-methoxyphenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (Example 391, PartA) (0.0375 g, 0.138 mmol) and 2-cyclopentylethylamine (0.0156 g, 0.138mmol) gives the title compound (0.034 g, 52.9%): TOF MS ES⁺ 370.2(M+H)⁺, base peak MS ES⁺ 257.1 (M−NHCH₂CH₂(C₅H₉))⁺, HRMS calcd forC₂₁H₂₈N₃O₃ 370.2123 (M+H)⁺, found 370.2155, time 0.38 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=10.5 min, 96.1%purity.

EXAMPLE 3995-(4-{[(Benzo[b]thiopben-3-ylmethyl)amino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.037g, 0.154 mmol) and benzo[b]thiophen-3-ylmethylamine (from thehydrochloride salt freed on a 1 g SCX column washing with methanol andeluting with 2.0 M NH₃ in methanol) (0.0485 g, 0.297 mmol) gives thetitle compound (0.0398 g, 53%): TOF MS ES⁺: TLC, 390.1 (M+H)⁺, HRMScalcd for C₂₂H₂₀N₃O₂S 390.1276 (M+H)⁺, found 390.1261, time 0.38 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=8.0 min.100% purity; Anal. Calcd for C₂₂H₁₉N₃O₂S 1.5CH₄O₃S: C, 52.89; H, 4.72;N, 7.72. Found: C, 52.69; H, 4.56; N, 7.72.

EXAMPLE 4005-(4-{[2-(4-Methoxyphenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.039g, 0.159 mmol) and 4-methoxyphenethylamine (0.023 mL, 0.159 mmol) givesthe title compound (0.0241 g, 32%): TOF MS ES⁺ 378.2 (M+H)⁺, HRMS calcdfor C₂₂H₂₄N₃O₃ 378.1818 (M+H)⁺, found 378.1836, time 0.39 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.2 min, 100%purity; Anal. Calcd for C₂₂H₂₃N₃O₃.1.1CH₄ 0 ₃S.0.4H₂O: C, 56.58; H,5.80; N. 8.52. Found: C, 56.18; H, 5.67; N, 8.20.

EXAMPLE 4015-(4-{[2-(3-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.040g, 0.164 mmol) and 3-fluorophenethylamine (0.024 mL, 0.181 mmol) givesthe title compound (0.044 g, 58.1%): TOF MS ES⁺ 366.2 (M+H)⁺, HRMS calcdfor C₂₁H₂₁N₃O₂F 366.1618 (M+H)⁺, found 366.1617, time 0.38 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.5 min, 100%purity.

EXAMPLE 4025-(4-{[2-(2-Fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.040g, 0.164 mmol) and 2-fluorophenethylamine (0.024 mL, 0.181 mmol) givesthe title compound (0.0324 g, 42.8%): TOF MS ES⁺ 366.2 (M+H)⁺, HRMScalcd for C₂₁H₂₁N₃O₂F 366.1618 (M+H)⁺, found 366.1623, time 0.38 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.3 min,100% purity.

EXAMPLE 4035-{2-Fluoro-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Part A: 5-(4-[1,3]Dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide

Take up 4-[1,3]dioxolan-2-yl-2-fluorophenol (Example 388, Part C2)(0.400 g, 2.14 mmol), 5-fluoropyridine-2-carboxamide (Example 388, PartC) (0.299 g, 2.14 mmol) and K₂CO₃ (0.514 g, 2.85 mmol) in DMF (5.3 mL).Beat at 100° C. overnight before concentrating to dryness. Take theblack tar up in dichloromethane and filter through a silica gel plug.Wash the plug with ethyl acetate (3×150 mL). Concentrate the filtrate.Purify by flash chromatography, eluting with 30-35% ethyl acetate indichloromethane until the 5-fluoropyridine-2-carboxamide elutes off thecolumn. Then elute with 100% ethyl acetate to give the title compound(0.317 g, 48.8%): MS ES⁺ 305.0 (M+H)⁺; TLC [silica gel 60 F₂₅₄, 30%ethyl acetate in dichloromethane] R_(f)=0.16.

Part B: 5-(2-Fluoro-4-formylphenoxy)pyridine-2-carboxamide

Take up 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide(0.316 g, 1.04 mmol) in 88% formic acid (5.2 mL). Stir at roomtemperature for 1.25 hours before diluting with water. Extract withdichloromethane (2×50 mL). Wash the organic layer with brine (1×25 mL),dry over Na₂SO₄, filter and concentrate to give the title compound(0.269 g, 99.6%): TOF MS ES⁺ 261.1 (M+H)⁺, HRMS calcd for C₁₃H₁₀N₂O₃F261.0675 (M+H)⁺, found 261.0682, time 0.37 min; HPLC [YMC-Pack Pro C-18(15×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R) 9.0 min, 100% purity.

Part C:5-{2-Fluoro-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, using5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (0.0326 g, 0.125mmol) and isoamylamine (0.0145 mL, 0.125 mmol) gives the title compound(0.0412 g, 69%): TOF MS ES⁺ 332.2 (M+H)⁺, HRMS calcd for C₁₈H₂₃N₃O₂F332.1774 (M+H)⁺, found 332.1787, time 0.39 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R)=6.7 min, 100% purity.

EXAMPLE 4045-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamidemethanesulfonate

Part A: 5-Chloropyrazine-2-carbonitrile

Dissolve 5-chloropyrazine-2-carboxamide (Example 389, Part A) (0.0878 g,0.557 mmol) in POCl₃ (5.6 mL) and heat at reflux for 35 minutes.Concentrate the reaction mixture. Take up the dark oil in saturatedaqueous NaHCO₃ (15 mL) and extract with dichloromethane (2×25 mL). Washthe organic layer with brine (1×15 mL), dry over Na₂SO₄, filter andconcentrate. Purify by flash chromatography, eluting with 10% ethylacetate in hexanes to give the title compound (0.0498 g, 64.0%): GC/MS,MS ES⁺ 139 (M)⁺, time 10.6 min, % of total 100%; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R) 8.2 min, 100% purity.

Part B: 5-(4-[1,3]dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carbonitrile

Take up 4-[1,3]dioxolan-2-yl-2-methylphenol (Example 388, Part C2)(0.288 g, 2.06 mmol), 5-chloropyrazine-2-carbonitrile (0.372 g, 2.06mmol) and K₂CO₃ (0.428 g 3.10 mmol) in DMF (13.8 mL). Heat at 100° C.for 45 minutes. Cool to 80° C. and stir overnight. Dilute the reactionmixture with dichloromethane (100 mL). Wash the organic layer withsaturated aqueous NaBCO₃ (2×25 mL) and brine (1×25 mL). Dry over Na₂CO₃,filter and concentrate. Purify by flash chromatography, eluting with 30%ethyl acetate in hexanes to give the title compound (0.560 g, 95.58%):TLC [silica gel 60 F₂₅₄, 30% ethyl acetate in hexanes] R_(f)=0.52.

Part C: 5-(4-[1,3]Dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carboxamide

Take up 5-(4-[1,3]dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carbonitrile(0.082 g, 0.305 mmol) and K₂CO₃ (0.020 g, 0.152 mmol) in DMSO (3.0 mL).Add 30% H₂O₂ (0.090 mL, 0.792 mmol) and stir at room temperature for 1.5hours before quenching with water (10 mL). Extract with ethyl acetate(50 mL). Wash the organic layer with water (1×10 mL), dry over Na₂SO₄filter and concentrate. Purify by flash chromatography eluting with 40%ethyl acetate in dichloromethane to give the title compound (0.063 g,68.6%): MS ES⁺ 302.0 (M+H)⁺; TLC [silica gel 60 F₂₅₄, 40% ethyl acetatein dichloromethane] R_(f)=0.17.

Part D: 5-(4-Formyl-2-methylphenoxy)pyrazine-2-carboxamide

Using a method similar to (Example 403, Part B), a reaction of5-(4-[1,3]dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carboxamide (0.055 g,0.183 mmol) gives the title compound (0.047 g, 100%): HPLC [YMC-Pack ProC-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/waterat 1.0 mL/min, 20-99% over 23 min], t_(R) 8.6 min, 100% purity; TLC[silica gel 60 F₂₅₄, 30% ethyl acetate in dichloromethane] R_(f)=0.22.

Part E:5-{2-Methyl-4-[(3-methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamidemethanesulfonate

Using a method similar to Example 389, a reaction of5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (0.0441 g, 0.171mmol) and isoamylamine (0.020 mL, 0.171 mmol) gives the title compound(0.0563 g, 77.5%): TOF MS ES⁺ 329.2 (M+H)⁺, HRMS calcd for C₁₈H₂₅N₄O₂329.1978 (M+H)⁺, found 329.1985, time 0.39 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min] t_(R)=6.4 min, 94.1% purity.

EXAMPLE 4055-(2-Fluoro-4-pentylaminomethylphenoxy)pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.040 g, 0.154 mmol) amylamine (0.0139 g, 0.154 mmol) and 3 Åmolecular sieves in a vial. Add methanol (1.5 mL), cap and stirovernight. Add NaBH₄ (in excess over two portions) and stir until thegasses stop evolving. Load directly onto a 5 g SCX column. Wash withmethanol (10 mL), then elute with 2.0 M NH₃ in methanol. Purify byloading the product onto a 5 g loading cartridge and eluting through a10 g ISCO® column with 50% ethyl acetate, 5% (2.0 M NH₃ in methanol) and45% hexanes to give the title compound (0.0387 g, 76.0%: TOF MS ES⁺332.2 (M+H)⁺, HRMS calcd for C₁₈H₂₃N₃O₂F 332.1774 (M+H)⁺, found332.1765, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99%over 23 min], t_(R)=6.9 min, 100% purity.

EXAMPLE 4065-{2-Fluoro-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B)(0.040 g, 0.154 mmol) and 2-(2-thienyl)ethylamine (0.0196 g, 0.154 mmol)gives the title compound (0.0344 g, 60.2%): TOF MS ES⁺ 372.1 (M+H)⁺,HRMS calcd for C₁₉H₁₉N₃O₂FS 372.1182 (M+H)⁺, found 372.1168, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=6.9 min, 100% purity.

EXAMPLE 4075-{2-Fluoro-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, a reaction of5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B)(0.040 g, 0.154 mmol) and 2-(pyridin-3-yl)ethylamine (0.019 g, 0.154mmol) gives the title compound (0.0463 g, 82.2%): TOF MS ES⁺ 367.2(M+H)⁺, HRMS calcd for C₂₀H₂₀N₄O₂F 367.1570 (M+H)⁺, found 367.1553, time0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min],t_(R)=6.9 min, 100% purity.

EXAMPLE 4085-{2-Fluoro-4-[(2-m-tolylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 405, Part B)(0.040 g, 0.154 mmol) and 3-methoxyphenethylamine (0.021 g, 0.154 mmol)gives the title compound (0.0306 g, 52.5%): TOF MS ES⁺ 380.2 (M+H)⁺,HRMS calcd for C₂₁H₂₃N₃O₂F 380.1774 (M+H)⁺, found 380.1757, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=8.4 min, 100% purity.

EXAMPLE 4095-(2-Fluoro-4-{[2-(4-fluorophenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B)(0.040 g, 0.154 mmol) and 4-fluorophenethylamine (0.021 g. 0.154 mmol)gives the title compound (0.0231 g, 39.2%): TOF MS ES⁺ 384.2 (M+H)⁺,HRMS calcd for C₂₁H₂₀N₃O₂F₂ 384.1524 (M+H)⁺. found 384.1509, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=7.8 min 100% purity.

EXAMPLE 4105-{2-Chloro-4-[(3-methylbutylamino)methyl]phenoxy}pyridine-2-carboxamide

Part A: 5-(2-Chloro-4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide

Using a method similar to Example 403, Part A, a reaction of2-chloro-4-[1,3]dioxolan-2-ylphenol (Example 388, Part C2) (0.429 g,2.14 mmol) and 5-fluoropyridine-2-carboxamide (Example 388 Part C)(0.299 g, 2.14 mmol) gives the title compound (0.264 g, 38.5%): MS ES⁺320.9 (M+H)⁺; TLC [silica gel 60 F₂₅₄, 30% ethyl acetate indichloromethane] R_(f)=0.19.

Part B: 5-(2-Chloro-4-formylphenoxy)pyridine-2-carboxamide

Using a method similar to Example 403, Part B, a reaction of5-(2-chloro-4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide (0.263 g,0.820 mmol) in 88% formic acid gives the title compound (0.194 g,85.5%): TOF MS ES⁺ 277.0 (M+H)⁺, HRMS calcd for C₁₃H₁₀N₂O₃Cl 277.0380(M+H)⁺, found 277.0378, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,20-99% over 23 min], t_(R)=10.3 min, 100% purity.

Part C:5-{2-Chloro-4-[(3-methylbutylamino)methyl]phenoxypyridine-2-carboxamide

Using a method similar to Example 405, a reaction of5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140mmol) and isoamylamine (0.012 g, 0.140 mmol) gives the title compound(0.0320 g, 65.6%): TOF MS ES⁺ 348.1 (M+H)⁺, HRMS calcd for C₁₈H₂₃N₃O₂Cl348.1479 (M+H)⁺, found 348.1466, time 0.39 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R)=7.4 min, 100% purity.

EXAMPLE 4115-(2-Chloro-4-(pentylaminomethyl)phenoxy)pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140mmol) and amylamine (0.012 g, 0.140 mmol) gives the title compound(0.0314 g, 64.3%): TOF MS ES⁺ 348.1 (M+H)⁺, HRMS calcd for C₁₈H₂₃N₃O₂Cl348.1479 (M+H)⁺, found 348.1456, time 0.39 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R)=7.6 min, 100% purity.

EXAMPLE 4125-{2-Chloro-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140mmol) and 2-(2-thienyl)ethylamine (0.018 g, 0.140 mmol) gives the titlecompound (0.0396 g, 72.8%): TOF MS ES⁺ 388.1 (M+H)⁺. HRMS calcd forC₁₉H₁₉N₃O₂ClS 388.0887 (M+H)⁺, found 388.0866, time 0.39 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.6 min, 100%purity.

EXAMPLE 4135-{2-Chloro-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140mmol) and 2-(pyridin-3-yl)ethylamine (0.017 g, 0.140 mmol) gives thetitle compound (0.0490 g, 91.2%): TOF MS ES⁺ 383.1 (M+H)⁺, HRMS calcdfor C₂₀H₂₀N₄O₂Cl 383.1275 (M+H)⁺, found 383.1248, time 0.39 min; Anal.Calcd for C₂₀H₁₉ClN₄O₂.0.1CH₂Cl₂: C, 61.90; H, 5.06; N, 14.38. Found: C.61.90; H, 5.06; N, 14.38.

EXAMPLE 4146-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide

Part A: 6-(4-Formyl-2-methoxyphenoxy)nicotinonitrile

Take up vanillin (1.0 g, 6.57 mmol), 6-chloronicotinonitrile (0.911 g,6.57 mmol) and K₂CO₃ (1.36 g, 9.86 mmol) in DMF (16.4 mL). Stir at roomtemperature overnight, then heat at 100° C. for 3 hours. Cool thereaction mixture to room temperature before quenching with water (75mL). Extract with dichloromethane (2×150 mL). Wash the organic layerwith brine (1×75 mL), dry over MgSO₄, filter and concentrate to give thetitle compound (1.65 g, 98.8%): TOF MS ES⁺ 255.1 (M+H)⁺, HRMS calcd forC₁₄H₁₁N₂O₃ 255.0770 (M+H)⁺, found 255.0776, time 0.38 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=12.2 min, 100%purity.

Part B: 6-(4-Formyl-2-methoxyphenoxy)nicotinamide

Using a method similar to (Example 404, Part C),6-(4-formyl-2-methoxyphenoxy)nicotinonitrile (1.53 g, 6.00 mmol) givesthe title compound (1.59 g, 97.5%): MS ES⁺ 273.0 (M+H)⁺, MS ES⁻ 271.1(M−H)⁻; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=7.2 min, 98.6% purity.

Part C: 6-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (0.0423 g, 0.155 mmol) andisoamylamine (0.020 g, 0.171 mmol) gives the title compound (0.0162 g,30.3%): TOF MS ES⁺ 344.2 (M+H)⁺, HRMS calcd for C₁₉H₂₆N₃O₃ 344.1974(M+H)⁺, found 344.1949, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,20-99% over 23 min], t_(R)=5.9 min, 100% purity.

Example 4155-(2-Fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide

Using a method similar to Example 405, a reaction of5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B)(0.0294 g, 0.113 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.016 g,0.124 mmol) gives the title compound (0.0187 g 44.2%): TOF MS ES⁺ 374.2(M+H)⁺, HRMS calcd for C₂₀H₂₅N₃O₃F 374.1880 (M+H)⁺, found 374.1863, time0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min],t_(R)=5.2 min, 95.2% purity.

EXAMPLE 4165-{2-Fluoro-4-[(2-o-tolylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B)(0.0294 g, 0.113 mmol) and 2-methylphenethylamine (0.017 g, 0.124 mmol)gives the title compound (0.0276 g, 65.2%): TOF MS ES⁺ 380.2 (M+H)⁺,HRMS calcd for C₂₂H₂₃N₃O₂F 380.1774 (M+H)⁺, found 380.1741, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min],t_(R)=8.2 min, 100% purity.

Example 4175-{4-[(2-Naphthalen-2-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, using5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366g, 0.151 mmol) and 2-naphthalen-2-ylethylamine (0.0286 g, 0.166 mmol)gives the title compound (0.0302 g, 50.3%): TOF MS ES⁺ 398.2 (M+H)⁺,HRMS calcd for C₂₅H₂₄N₃O₂ 398.1869 (M+H)⁺, found 398.1833, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min],t_(R)=9.2 min, 98.0% purity.

EXAMPLE 4185-{4-[(2-Naphthalen-1-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, a reaction of5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366g, 0.151 mmol) and 2-naphthalen-1-ylethylamine (0.0285 g, 0.166 mmol)gives the title compound (0.0160 g, 26.7%): TOF MS ES⁺ 398.2 (M+H)⁺,HRMS calcd for C₂₅H₂₄N₃O₂ 398.1869 (M+H)⁺, found 398.1855, time 0.39min; TLC [silica gel 60 F₂₅₄, 4% (2.0 M NH₃ in methanol) in ethylacetate] R_(f)=0.26.

EXAMPLE 4195-{4-[(2-Benzo[b]thiophen-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Part A: 2-Benzo[b]thiophen-3-ylethylamine

Reduce benzo[b]thiophen-3-yl-acetonitrile (350.9 mg, 2.0 mmol) in Et₂O(6.0 mL) with 1.0 M LAH in THF (6.0 mL) at 0-10° C. for 1 hour. Carryout Fieser work-up to remove the LAH. Concentrate and pass through anSCX column, washing with MeOH and then eluting with 2.0 M NH₃ in MeOH.Concentrate the eluant and purify twice by chromatography, eluting with75:20:5 EtOAc/hexanes/2.0 M NH₃ in MeOH and then with 70:20:10EtOAc/hexanes/2.0 M NH₃ in MeOH to yield the title compound (86.5 mg,24%): MS ES₊ 178.2 (M+H)⁺, 161.2 (base peak); ¹H NMR (DMSO-d₆) δ 7.94(d, J=7.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.40-7.33 (m, 3H), 3.32 (brs, 2H), 2.88 (br s, 4H).

Part B:5-{4-[(2-Benzo[b]thiophen-3-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Using a method similar to Example 405, a reaction of5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366g, 0.151 mmol) and 2-benzo[b]thiophen-3-ylethylamine (0.0295 g, 0.166mmol) gives the title compound (0.0306 g, 50.2%): TOF MS ES⁺ 404.1(M+H)⁺, HRMS calcd for C₂₃H₂₂N₃O₂S 404.1433 (M+H)⁺, found 404.1423, time0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=8.9 min. 100% purity.

EXAMPLE 420 6-(2-Methoxy-4-pentylaminomethylphenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and amylamine (0.016 g, 0.184 mmol) gives the titlecompound (0.0426 g, 67.5%) TOFMS ES⁺ 344.2 (M+H)⁺, HRMS calcd forC₁₉H₂₆N₃O₃ 344.1974 (M+H)⁺, found 344.1963time 0.41 min; HPLC [YMC-PackPro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=6.1 min, 100%purity.

EXAMPLE 4216-{2-Methoxy-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-(2-thienyl)ethylamine (0.0234 g, 0.184 mmol) givesthe title compound (0.0495 g, 70.3%): TOF MS ES⁺ 384.1 (M+H)⁺, HRMScalcd for C₂₀H₂₂N₃O₃S 384.1382 (M+H)⁺, found 384.1375, time 0.39 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitiilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=6.1 min,100% purity.

EXAMPLE 4226-{2-Methoxy-4-[(2-o-tolylethylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-methylphenethylamine (0.0248 g, 0.184 mmol) givesthe title compound (0.0584 g. 81.2%): TOF MS ES⁺ 392.2 (M+H)⁺, HRMScalcd for C₂₃H₂₆N₃O₃ 392.1974 (M+H)⁺, found 392.1966, time 0.39 min HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.5 min, 97.6%purity.

EXAMPLE 4236-{2-Methoxy-4-[(2-m-tolylethylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 3-methylphenethylamine (0.0248 g, 0.184 mmol) givesthe title compound (0.0568 g, 78.9%): TOF MS ES⁺ 392.2 (M+H)⁺, HRMScalcd for C₂₃H₂₆N₃O₃ 392.1974 (M+H)⁺, found 392.1975, time 0.41 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.7 min,97.6% purity.

EXAMPLE 4246-{4-[(3,3-Dimethylbutylamino)methyl]-2-metlhoxyphenoxy}nicotinamide

Using a method similar to Example 405 using6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 3,3-dimethylbutylamine (0.0186 g, 0.184 mmol) givesthe title compound (0.0205 g, 31.3%): TOF MS ES⁺ 358.2 (M+H)⁺, HRMScalcd for C₂₀H₂₈N₃O₃ 358.2131 (M+H)⁺, found 358.2131, time 0.41 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=6.8 min,100% purity.

EXAMPLE 4256-{2-Methoxy-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-(pyridin-3-yl)ethylamine (0.0224 g, 0.184 mmol)gives the title compound (0.0406 g, 58.4%): TOF MS ES⁺ 379.2 (M+H)⁺,HRMS calcd for C₂₁H₂₃N₄O₃ 379.1770 (M+H)⁺, found 379.1759, time 0.41min.

EXAMPLE 426 6-(4-Butylaminomethyl-2-methoxyphenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and n-butylamine (0.0134 g, 0.184 mmol) gives the titlecompound (0.0458 g, 75.7%): TOF MS ES⁺ 330.2 (M+H)⁺, HRMS calcd forC₁₈H₂₄N₃O₃ 330.1818 (M+H)⁺, found 330.1802, time 0.39 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=4.9 min, 100%purity.

EXAMPLE 4276-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.0237 g, 0.184mmol) gives the title compound (0.0545 g, 77.0%): TOF MS ES⁺ 386.2(M+H)⁺, HRMS calcd for C₂₁H₂₈N₃O₄ 386.2080 (M+H)⁺, found 386.2076, time0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=4.3 min, 100% purity.

EXAMPLE 4286-{2-Methoxy-4-[(2-morpholin-4-ylethylamino)methyl]phenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-morpholin-4-ylethylamine (0.0224 g, 0.184 mmol)gives the title compound (0.0347 g, 49.0%): TOF MS ES⁺ 387.2 (M+H)⁺,HRMS calcd for C₂₀H₂₇N₄O₄ 387.2032 (M+H)⁺, found 387.2023, time 0.41min; ¹H NMR (DMSO-d₆) δ 8.51 (d. J=2.0 Hz, 1H), 8.19 (dd, J=8.8, 2.4 Hz,1H), 7.98 (s, 2H), 7.43 (s, 1H), 7.11 (d, J=1.95 Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 6.98 (d, J=8.3 Hz, 1H) 6.91 (dd, J=8.1, 1.7 Hz, 1H) 3.72 (s,2H), 3.66 (s, 3H), 3.55 (t, J=4.6 Hz, 4H), 2.63 (t, J=6.6 Hz, 2H), 2.41(t, J=6.3 Hz, 2H), 2.34 (s, 4H).

EXAMPLE 4296-{4-[(2-Ethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-ethylbutylamine (0.0186 g, 0.184 mmol) gives thetitle compound (0.0450 g, 68.6%): TOF MS ES⁺ 358.2 (M+H)⁺. HRMS calcdfor C₂₀II₂₈N₃O₃ 358.2131 (M+H)⁺, found 358.2127, time 0.41 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=6.6 min, 98.8%purity.

EXAMPLE 4306-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 4-fluorophenethylamine (0.0256 g, 0.184 mmol) givesthe title compound (0.0689 g. 94.9%): TOF MS ES⁺ 396.2 (M+H)⁺, HRMScalcd for C₂₂H₂₃N₃O₃F 396.1723 (M+H)⁺found 396.1714, time 0.41 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.1 min, 100%purity.

EXAMPLE 4316-(4-{[2-(2-Fluorophenyl)ethylamino)methyl}-2-methoxyphenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and 2-fluorophenethylamine (0.0256 g, 0.184 mmol) givesthe title compound (0.0615 g, 84.7%): TOF MS ES⁺ 396.2 (M+H)⁺, HRMScalcd for C₂₂H₂₃N₃O₃F 396.1723 (M+H)⁺, found 396.1722, min 0.39; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=6.8 min, 98.9%purity.

EXAMPLE 432 6-(4-Hexylaminomethyl-2-methoxyphenoxy)nicotinamide

Using a method similar to Example 405, a reaction of6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050g, 0.184 mmol) and hexylamine (0.0186 g, 0.184 mmol) gives the titlecompound (0.0479 g, 73.0%): TOF MS ES⁺ 358.2 (M+H)⁺. HRMS calcd forC₂₀H₂₈N₃O₃ 358.2131 (M+H)⁺, found 358.2124, time 0.41 min HPLC [YMC-PackPro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.4 min, 100%purity.

EXAMPLE 4336-{2-Methoxy-4-[(4-methylpentylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Part A: 4-Methylpentylamine

Stir a mixture of 4-methylpentanol (2.0 mL, 16.0 mmol), Et₃N (4.5 mL,32.1 mmol), and TsCl (3.676 g, 19.2 mmol) in CH₂Cl₂ (30 mL) at roomtemperature for 2 days. Quench the reaction with H₂O, take up themixture in Et₂O (250 mL), and wash with 2.0 N HCl, H₂O, 2.0 N NaOH, H₂Oand brine (100 mL each) consecutively. Back-extract the aqueous washingswith Et₂O (200 mL). Combine the organic layers, dry over MgSO₄ andconcentrate.

Dissolve the tosylate obtained in 7.0 N NH₃ in MeOH (200 mL) at 0° C.Stir for 5 days, while allowed to warm to room temperature. Concentrateand purify on an SCX column, washing with MeOH, then eluting with 2.0 MNH₃ in MeOH. Repeat the process three times till no amine was observedin MeOH washings. Combine the eluants and carefully distill to collectthe title amine (610.7 mg, 37%): bp 90-110° C.; GCMS 101 (M)⁺, 4.46 min.

Part B: 6-{2-Methoxy-4-[(4-methylpentylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.100 g, 0.367 mmol), 4-methylpentylamine (Part A, 0.0409 g, 0.404mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap andstir overnight. Add NaBH₄ (in excess over two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 5 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 10 g ISCO® column with (2.0 MNH₃ in methanol) in ethyl acetate to give6-{2-methoxy-4-[(4-methylpentylamino)methyl]phenoxy}nicotinamide (0.131g, 71.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1equivalent of 0.50M methanesulfonic acid in dichloromethane. Stir thesolution for a short time before concentrating to give the titlecompound (0.124 g, ˜100%): TOF MS ES⁺ 358.2 (M+H)⁺, HRMS calcd forC₂₀H₂₈N₃O₃ 358.2131 (M+H)⁺, found 358.2119, time 0.39 min; HPLC [WatersXTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 15 min], t_(R)=8.2 min, 100% purity.

EXAMPLE 4346-{2-Methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.100 g, 0.367 mmol), 2-p-tolylethylamine (0.0546 g, 0.404 mmol) and 3Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stirovernight. Add NaBH₄ (in excess over two portions) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 5 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 10 g ISCO® column with (2.0 MNH₃ in methanol) in ethyl acetate to give6-{2-methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamide (0.143g, 97.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir thesolution for a short time before concentrating to give the titlecompound (0.168 g, ˜100%): TOF MS ES⁺ 392.1 (M+H)⁺, HRMS calcd forC₂₃H₂₆N₃O₃ 392.1974 (M+H)⁺, found 392.1966, time 0.39 min; HPLC [WatersXTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 15 min], t_(R)=8.4 min, 100% purity.

EXAMPLE 4355-(2-Methyl-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide

Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404,Part D) (0.200 g, 0.777 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.100g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8mL), cap and stir overnight. Add NaBH₄ (in excess over two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuumoven at room temperature. Purify by eluting through a 10 g ISCO® columnwith (2.0 M NH₃ in methanol), ethyl acetate and hexanes. Afterconcentrating, take the product up in CH₂Cl₂ (25 mL) and wash with 1.0 NNaOH solution (2×10 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate to give the title compound (0.121 g, 42.0%): MS ES⁺ 371.1(M+H)⁺, base peak 242.0 (M−C₇H₁₄NO)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 19 min], t_(R)=7.9 min, 100% purity.

EXAMPLE 4365-{4-[(3,3-Dimethylbutylamino)methyl]-2-methylphenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404,Part D) (0.200 g, 0.777 mmol), 3,3-dimethylbutylamine (0.100 g, 0.777mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap andstir overnight. Add NaBH₄ (in excess over two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 5 gISCO® pre-load column. Dry the pre-loaded column in a vacuum oven atroom temperature. Purify by eluting through a 10 g ISCO® column with(2.0 M NH₃ in methanol), ethyl acetate and hexanes. After concentrating,take the product up in CH₂Cl₂ (25 mL) and wash with 1.0 N NaOH solution(2×10 mL). Dry the organic layer over Na₂SO₄, filter and concentrate togive the title compound (0.110 g, 41.4%): MS ES⁺ 343.1 (M+H)⁺, base peak242.0 (M−C₆H₁₄N)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19min], t_(R)=9.7 min, 94.3% purity.

EXAMPLE 4375-{4-[(3-Methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide

Part A: 5-(4-Formylphenoxy)pyrazine-2-carbonitrile

Dissolve 4-[1,3]dioxolan-2-yl-2-phenol (Example 388, Part C2) (1.70 g,10.2 mmol), 5-chloropyrazine-2-carbonitrile (Example 404, Part A) (1.50g, 10.7 mmol) and K₂CO₃ (3.71 g, 26.9 mmol) in DMA (27.0 mL) andisooctane (13.4 mL). Heat at 110° C. for about 2.25 hours. Cool to roomtemperature and quench with water (100 mL). Extract with dichloromethane(3×100 mL). Wash the extract with saturated aqueous NaHCO₃ (1×50 mL) andbrine (1×75 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify by flash chromatography, eluting with 0-30% ethylacetate in hexanes. Concentrate the eluant, then take the solid up in88% formic acid (46 mL) and stir at room temperature for 4 hours. Dilutethe reaction mixture with water (50 mL). Extract with dichloromethane(2×100 mL). Wash the extract with saturated aqueous NaHCO₃ (1×50 mL),dry over Na₂SO₄, filter and concentrate. Purify by flash chromatographyeluting with 30% ethyl acetate in hexanes to give the title compound(1.88 g, 77.7%): TOF MS ES⁺ 225.1 (M)⁺, HRMS calcd for C₁₂H₇N₃O₂225.0538 (M)⁺, found 225.0527, time 0.38 min; HPLC [YMC-Pack Pro C-18(150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0mL/min, 20-99% over 23 min], t_(R)=11.5 min, 100% purity.

Part B: 5-(4-Formylphenoxy)pyrazine-2-carboxamide

Dissolve 5-(4-formylphenoxy)pyrazine-2-carbonitrile (1.87 g, 8.30 mmol)and K₂CO₃ (0.573 g, 4.15 mmol) in DMSO (21 mL). Add 30% H₂O₂ (2.4 mL,20.8 mmol) and stir at room temperature for 22 hours. Add additionalK₂CO₃ (0.573 g, 4.15 mmol) and heat at 55° C for about 2.5 hours. Coolthe reaction mixture and dilute with CH₂Cl₂, (200 mL). Wash with water(1×100 (mL) and saturated aqueous NaHCO₃ (1×100 mL). Dry the organiclayer over Na₂SO₄, filter and concentrate. Purify by flashchromatography, eluting with 0-50% ethyl acetate in dichloromethane togive the title compound (0.478 g, 23.7%): TOF MS ES⁺ 244.1 (M+H)⁺, HRMScalcd for C₁₂H₁₀N₃ ₃ 244.0722 (M+H)⁺, found 244.0709, time 0.38 min;HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], t_(R)=7.2 min,100% purity.

Part C: 5-{4-[(3-Methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (0.150 g, 0.617 mmol),3-methylbutylamine (0.0537 g, 0.617 mmol) and 3 Å molecular sieves in avial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH₄ (inexcess over two portions) and stir until the gasses stop evolving. Loadthe reaction mixture directly onto a 5 g ISCO® pre-load column. Dry thecolumn in a vacuum oven at room temperature. Purify by eluting through a10 g ISCO® column with 2.0 M NH₃ in methanol, ethyl acetate and hexanesto give the title compound (0.0606 g, 31.2%): MS ES⁺ 315.1 (M+H)⁺, basepeak 228.0 (M−C₅H₁₂N)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=8.5 min., 96.4% purity.

EXAMPLE 4385-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide

Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B)(0.150 g, 0.617 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0797 g,0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL),cap and stir overnight. Add NaBH₄ (in excess over two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 5 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 10 g ISCO® column with 2.0 MNH₃ in methanol and ethyl acetate. After concentrating, take the productup in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10mL). Dry the organic layer over Na₂SO₄, filter and concentrate to givethe title compound (0.0819 g, 37.2%): MS ES⁺ 357.1 (M+H)⁺, base peak228.0 (M−C₇H₁₄NO)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm),0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19min], t_(R)=7.4 min, 100% purity.

EXAMPLE 4395-{4-[(3,3-Dimethylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B)(0.150 g, 0.617 mmol), 3,3-dimethylbutylamine (0.0624 g, 0.617 mmol) and3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stirovernight. Add NaBH₄ (in excess over two portions) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 5 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 10 g ISCO® column with 2.0 MNH₃ in methanol, ethyl acetate and hexanes. After concentrating, takethe product up in dichloromethane (25 mL) and wash with 1.0 N NaOHsolution (2×10 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate to give the title compound (0.0687 g, 33.8%): MS ES⁺ 329.1(M+H)⁺, base peak 228.0 (M−C₆H₁₅N)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 19 min], t_(R)=9.2 min, 100% purity.

EXAMPLE 4406-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamidemethanesulfonate

Dissolve6-(2-methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide(Example 427) (0.612,1.59 mmol) in THF (4 mL) and few drops of methanolto form a clear solution. Add 1.27 M methanesulfonic acid (1.25 mL, 1.59mmol) in THF. Stir for 10 minutes, then concentrate to give the titlecompound (0.749 g, ˜100%): TOF MS ES⁺ 386.2 (M+H)⁺, HRMS calcd forC₂₁H₂₈N₃O₄ 386.2080 (M+H)⁺, found 386.2083, time 0.62 min; HPLC [WatersXTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 15 min], t_(R)=6.6 min, 100% purity.

EXAMPLE 441 6-(4-Hexylaminomethyl-2-methoxyphenoxy)nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-(4-hexylaminomethyl-2-methoxyphenoxy)nicotinamide (Example 432) thetitle compound is obtained.

EXAMPLE 442 6-(2-Methoxy-4-pentylaminomethylphenoxy)nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-(2-methoxy-4-pentylaminomethylphenoxy)nicotinamide (Example 420) thetitle compound is obtained.

EXAMPLE 443 6-(4-Butylaminomethyl-2-methoxyphenoxy)nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-(4-butylaminomethyl-2-methoxyphenoxy)nicotinamide (Example 426) thetitle compound is obtained.

EXAMPLE 4446-{2-Methoxy-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-{2-methoxy-4-[(2-pyridin-3-ylethylamino)methyl]phenoxy}nicotinamide(Example 425) the title compound is obtained.

EXAMPLE 4456-{4-[(2-Ethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-{4-[(2-ethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide (Example429) the title compound is obtained.

EXAMPLE 4466-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-{4-[(3,3-dimethylbutylamino)methyl]-2-methoxyphenoxy}nicotinamide(Example 424) the title compound is obtained.

EXAMPLE 446A6-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Using a procedure similar to that of Example 440, using6-{2-methoxy-4-[(3-methylbutylamino)methyl]phenoxy}nicotinamide (Example414, Part C) the title compound is obtained.

EXAMPLE 4476-(2-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Part A: 7-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one

Dissolve 4-hydroxytetralone (50 g, 284 mmol) in methanesulfonic acid(400 mL) and chill to 2° C. in an ice bath. Add sodium azide (24 g, 369mmol) in 3-gram portions over a period of 3 hours while keeping thetemperature below 5° C. Stir the solution cold for an additional hourand allow gradually warm to room temperature by removing the ice bath.Stir the solution for 16 hours. Pour the mixture into 3 L of crushed iceand add saturated aqueous NaHCO₃ until a pH of 8 is achieved. Add EtOAc(4 L) and extract 3 times. Dry the organic layer over MgSO₄ andconcentrate to a white solid. Chromatography on a Biotage® 75 S column(eluant 10:1 hexanes/EtOAc) provides the title compound as a white solid(27.3 g, 50% of theory). ¹H NMR (DMSO-d₆) δ 7.90 (br t, 1 H), 7.48 (d, 1H), 6.89 (m, 2 H), 3.72 (s, 3 H), 2.90 (m, 2 H), 2.59 (t, 2 H) 1.83 (m,2 H).

Part B: 7-Methoxy-2,3,4,5,5-tetrahydro-benzo[c]azepine

Add 7-methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one from step A (10 g,53 mmol) to THF (50 mL) under a nitrogen atmosphere. Stir and chill thesolution to 0° C. in an ice bath and add drop wise borane-THF complex(1.56 ml, 1.0 M in THF, 156 mmol ). After complete addition, heat thesolution at reflux for 2 hours and then cool to room temperature. Quenchthe reaction with 1.0 N HCl solution. Adjust the pH to 9 with 1.0 N NaOHsolution and add 300 mL of EtOAc. Extract the solution, dry the organiclayer over MgSO₄ and concentrate to a yellow oil. Chromatography on aBiotage® 75 S column (10% MeOH/DCM) yields the title compound as a whitesolid (4.2 g; 45% of theory). ¹H NMR (DMSO-d₆) δ 7.00 (d, 1 H), 6.63 (s,1 H), 6.59 (dd, 1 H), 3.69 (s, 2 H), 3.67 (s, 3 H), 3.02 (t, 2 H), 2.72(m, 2 H), 1.55 (m, 2 H). MS (EI) 178.2 m/z (M+1)

Part C: 2,3,4,5-Tetrahydro-1H-benzo[c]azepin-7-ol Hydrobromide

Dissolve product from Step B above (4.2 g, 22 mmol) in CH₂Cl₂ (50 mL)and add to BBr₃ (67 mmol, 6.4 mL) in CH₂Cl₂ (20 mL) at −78° C. under anitrogen atmosphere. Stir the reaction mixture at −70° C. for 2 hoursand then at room temperature for 16 hours. Cool the clear solution to−78° C. and carefully add methanol (15 mL). Concentrate the solution toa brown solid. Dissolved the solid in methanol (50 mL) and add CH₂Cl₂(40 mL). Concentrate the solution to half-volume and add hexanes (40mL). Concentrate again to half volume and add EtOAc (20 mL). Concentrateto a volume to 20 mL and filter to obtain a white granular solid (4.2 g,45% of theory): ¹H NMR (DMSO-d₆) δ 9.52 (s, 1H), 8.70 (br, 2H), 7.19 (d,1H), 6.58 (m, 2H), 4.23 (s, 2H), 3.33 (m, 2H), 2.88 (m, 2H), 1.70 (m,2H). MS (ES) 164.1 m/z (M+1). Elemental analysis Calc C, 49.19; H, 5.78;N, 5.55; Found C, 49.48; H, 5.78; N, 5.55.

Part D: N-tert-Butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ol

Mix product from Step C above (6.50 g, 26 mmol) with CH₂Cl₂ (100 mL) toform a slurry. Add triethylamine (79 mmol) and cool the slurry to 5° C.in an ice bath. Dissolve di-tert-butyl dicarbonate in CH₂Cl₂ (20 mL) andadd drop wise to the solution. Remove the ice bath and allow thesolution to stir at room temperature for four hours. Concentrate thesolution to a brown solid. Add 40 ml of a 1:1 CH₂Cl₂/EtOAc solution andfilter. Concentrate the filtrate to a brown oil and chromatograph (20%EtOAc/hexanes) to give a white solid (6.3 g, 90% of theory): ¹H NMR(DMSO-d₆) δ 9.15 (s, 1H), 6.97 (d, 1H), 6.60 (s, 1H), 6.49 (d, 1H), 4.23(s, 2H), 3.52 (br m, 2H), 2.72 (br m, 2H), 1.59 (br m, 2H), 1.33 (s,9H). ¹³C NMR (DMSO-d₆) δ 156.24, 142.99, 129.41, 116.41, 111.57, 78.29,50.95,49.57, 34.58, 28.02. Anal. Calcd for C₁₅H₂₁NO₃: C, 68.42; H, 8.04;N, 5.32. Found: C, 68.54; H, 8.15; N, 5.24.

Part E: 6-(2,3,4,5-Tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Add 80% NaH in mineral oil (28.3 mg, 0.94 mmol) to a solution of thebenzazepinol in Part D (124.3 mg, 0.47 mmol) in anhydrous DMF (2.0 mL)and stir for 30 minutes at room temperature. Add 6-chloronicotinamide(147.8 mg, 0.94 mmol) in one portion and stir overnight at roomtemperature and then heat at 80° C. for 3 hours. Quench the reactionwith water and concentrate. Purify by flash chromatography, eluting with40% CH₂Cl₂ in EtOAc.

Dissolve the above-coupled product in CH₂Cl₂ (2.5 mL) and treat withtrifluoroacetic acid (2.5 mL) at room temperature for one hour.Concentrate the mixture and purify by an SCX column, washing withmethanol and then eluting with 2.0 M NH₃ in MeOH to yield the titlecompound (109.3 mg, 82% for 2 steps): MS ES⁺ 284.0 (M−H)⁺; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], t_(R)=6.99 min, 100%purity.

Part F:6-(2-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (PartE, 112.9 mg, 0.40 mmol), K₂CO₃ (110.1 mg, 0.80 mmol), and phenethylbromide (82 uL 0.60 mmol) in DMF (2.0 mL). Heat at 70-80° C. overnight.Remove DMF azeotropically with xylenes. Purify by flash chromatography,eluting with 75:19:6 EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH and then with60:30:10 EtOAc/hexanes/2.0 M NH₃ in MeOH. Purify by reverse phasechromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1%TFA/water to give the title compound (44.9 mg, 27% from Step D): MS ES⁺284.0 (M−H)⁺; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min],t_(R)=9.85 min, 100% purity; Anal. Calcd for C₂₄H₂₅N₃O₂.0.1H₂O.0.1MeOH:C, 73.75; H, 6.57; N, 10.71. Found: C, 73.45; H, 6.62; N, 10.72.

EXAMPLE 4486-[2-(3-Methylbutyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 50.7 mg, 0.18 mmol), K₂CO₃ (49.5 mg, 0.36 mmol),and isoamyl bromide (32 uL, 0.27 mmol) in DMF (1.0 mL). Heat at 80° C.for 6 hours. Pass through an SCX column, washing with methanol and theneluting with 2.0 M NH₃ in MeOH. Concentrate the eluant and purify byflash chromatography, eluting with 70:22:8 EtOAc/CH₂Cl₂/2.0 M NH₃ inMeOH to afford the title compound (45.7 mg, 72%): MS ES⁺ 354.0 (M+H)⁺,HRMS calcd for C₂₁H₂₈N₃O₂ 354.2182 (M+H)⁺, found 354.2182, time 0.39min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min],t_(R)=6.39 min, 100% purity; Anal. Calcd forC₂₁H₂₇N₃O₂.0.2CH₂Cl₂.0.1MeOH: C, 69.59; H, 5.98; N, 11.43. Found: C,69.47; H, 6.25; N, 11.30.

EXAMPLE 4496-[2-(3-Methylpentyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 55.6 mg, 0.20 mmol), K₂CO₃ (54.2 mg, 0.39 mmol),and 1-bromo-4-methylpentane (43 uL, 0.29 mmol) in DMF (1.0 mL). Heat at80° C. overnight. Remove DMF azeotropically with xylenes. Purify byflash chromatography, eluting with 70:25:5 EtOAc/CH₂Cl₂/2.0 M NH₃ inMeOH to afford the title compound (43.1 mg, 60%): MS ES⁺ 368.4 (M+H)⁺,HRMS calcd for C₂₂H₃₀N₃O₂ 368.2338 (M+H)⁺, found 368.2330, time 0.39min; Anal. Calcd for C₂₂H₂₉N₃O₂.0.1CH₂Cl₂0.1MeOH: C, 70.32; H, 7.87; N,11.08. Found: C, 70.05; H, 7.52; N, 11.01.

EXAMPLE 450(±)-6-{4-[2-(2-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Part A: (±)-4-[2-(2-Hydroxycyclohexylamino)ethyl]phenol

Mix (±)-2-aminocyclohexanol (1.5227 g, 13.2 mmol), K₂CO₃ (4.56 g, 33.0mmol), and 1-(2-chloroethyl)-4-methoxybenzene (2.0 mL, 13.2 mmol) in DMF(30 mL). Heat at 100° C. for 24 hours. Cool down to room temperature andfiltrate with MeOH wash. Concentrate and remove DMF azeotropically withxylenes. Take up the residue in CH₂Cl₂ and H₂O (100 mL each). Separatethe layers and extract the aqueous layer with CH₂Cl₂ (2×100 mL). Washthe organic layers with H₂O and brine (100 mL each). Dry the combinedorganic layers over MgSO₄, concentrate and purify by flashchromatography, eluting with 50:45:5 EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH toafford 2-(4-methoxyphenethylamino)cyclohexanol. (1.38 g, 42%).

Mix the methoxy ether (505.9 mg, 2.0 mmol) and 1.0 M BBr₃ in heptane(4.0 mL, 4.0 mmol) in CH₂Cl₂ (10 mL in total). Stir the mixture at 0-17°C. for 3 hours. Quench the reaction with saturated aqueous NaHCO₃ (30mL) at 0° C. Take up the mixture in saturated aqueous NaHCO₃ (20 mL) andCH₂Cl₂ (30 mL). Dissolve the precipitate formed with CH₂Cl₂ and a smallamount of MeOH. Separate the layers after vigorously shaking. Wash theorganic layer with 1:1 saturated aqueous NaHCO₃/brine (50 mL).Back-extract the aqueous layers with CH₂Cl₂ (2×50 mL) and 10% MeOH inCH₂Cl₂ (5×). Dry the combined organic layers over MgSO₄, concentrate andpurify by flash chromatography, eluting with 75:15:10 EtOAc/CH₂Cl₂/2.0 MNH3 in MeOH (375.8 mg, 79%): MS ES⁺ 236.1 (M+H)⁺, ES⁻ 234.2 (M−H)⁻; ¹HNMR (DMSO-d₆) δ 9.11 (s, 1H), 6.97 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.3 Hz,2H), 4.41 (d, J=4.4 Hz, 1H), 3.32 (s, 1H), 3.03 (s, 1H), 2.76 (m, 1H),2.55 (m, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H), 1.54 (m, 2H),1.13 (m, 3H), 0.86 (m, 1H).

Part B: (±)-6-{4-[2-(2-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Heat a mixture of 4-[2-(2-hydroxycyclohexylamino)ethyl]phenol (152.6 mg,0.65 mmol), 6-chloronicotinamide (84.6 mg, 0.54 mmol) and K₂CO₃ (186.7mg, 1.35 mmol) in 3:1 DMF/toluene (4.0 mL) at 160° C. for 2 hours. Coolto room temperature and filter with thorough MeOH and CH₂Cl₂ wash.Concentrate the filtrate and remove DMF azeotropically with xylenes.Purify by flash chromatography, eluting with 75:15:10 EtOAc/CH₂Cl₂/2.0 MNH₃ in MeOH (56.3 mg, 29%): MS ES⁺ 356.1 (M+H)⁺, HRMS calcd forC₂₀H₂₆N₃O₃ 356.1974 (M+H)⁺, found 356.1966, time 0.37 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min],t_(R)=1.23 min, 100% purity; Chiralpak AD 225 min, 60:40 EtOH/heptane at1.0 mL/min, t_(R)=5.55 min, 50% and t_(R)=7.17 min, 50%; Anal. Calcd forC₂₀H₂₅N₃O₃.0.2CH₂Cl₂.0.2MeOH: C, 64.68; H, 6.97; N, 11.09. Found: C,64.46; H, 6.84; N, 11.11.

EXAMPLE 451(±)-(cis)-6-{4-[2-(3-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Part A: 3-(tert-Butyldimethylsilyloxy)cyclohexanone

Stir a mixture of 1,3-cyclohexanediol (250.9 mg, 2.16 mmol) and NaH (80%in mineral oil, 71.3 mg, 2.38 mmol) in freshly distilled THF (5.0 mL)for 30 minutes. Add tert-butyldimethylsilyl chloride (325.5 mg, 2.16mmol) in THF (2.0 mL in total). Stir for 2 hours, add THF (3.0 mL) tothe milky solution, and stir overnight. Quench the reaction with brineand extract with EtOAc (3×30 mL). Combine extracts, dry over MgSO₄, andconcentrate. Flash chromatography, eluting with 30% Et₂O/hexanes yieldsa mono-silyl ether (185.5 mg, 37%).

Add PCC (344 mg, 1.6 mmol) to the mono-protected cyclohexanediol (183.8mg, 0.8 mmol) in anhydrous CH₂Cl₂ (10 mL) at room temperature and stirovernight. Filter through a Celite® pad with thorough CH₂Cl₂ rinse. Washthe filtrate with saturated aqueous NaHCO₃ and brine (30 mL each).Back-extract the aqueous layers with CH₂Cl₂ (2×30 mL). Combine theorganic layers, dry over MgSO₄, concentrate and purify by flashchromatography, eluting with 20% Et₂O/hexanes to afford the titlecompound (150.7 mg, 83%): HRMS calcd for C₁₂H₂₄O₂NaSi 251.1443 (M+Na)⁺,found 251.1432, time 0.43 min; IR (cm⁻¹) 1711 (C═O).

Part B: 6-[4-(2-Aminoethyl)phenoxy]nicotinamide

Treat [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (534.3mg, 2.2 mmol) with NaH (80% in mineral oil, 78.0 mg (2.6 mmol) inanhydrous DMF (10 mL) at room temperature for 30 minutes. Add6-chloronicotinamide (343.8 mg, 2.2 mmol) and heat the mixture at 80° C.overnight. Quench the reaction with H₂O and concentrate to dryness,using xylenes to remove DMF as an azeotrope. Suspend the residue in MeOHand filter with thorough MeOH and CH₂Cl₂ rinse. Concentrate the filtrateand purify by flash chromatography, eluting with 75:15:10EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH. Deprotect the BOC group with 1:1TFA/CH₂Cl₂ (16 mL) at room temperature overnight. Concentrate and purifyby an SCX column, washing with MeOH and then eluting with 2.0 M NH₃ inMeOH: MS ES⁺ 297.9 (M+H+K)⁺, HRMS calcd for Cl₁₄H₁₆N₃O₂ 258.1243 (M+H)⁺,found 258.1235, time 0.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95%over 19 min], t_(R)=6.93 min, 100% purity.

Part C: (±)-(cis)- and(trans)-6-(4-{2-[3-(tert-Butyldimethyl-siyloxy)cyclohexylamino]ethyl}phenoxy)nicotinamide

Dissolve 6-[4-(2-aminoethyl)phenoxy]nicotinamide (121.4 mg, 0.472 mmol)in MeOH (0.48 mL) and dichloroethane (1.0 mL). Add3-(tert-butyldimethylsilyloxy)cyclohexanone (151 mg, 0.661 mmol) indichloroethane (2.0 mL). Add the mixture to a solution of NaB(OAc)₃H(140 mg, 0.661 mmol) in dichloroethane (1.3 mL). After 10 minutes, adddropwise AcOH (27 uL, 0.472 mmol) and stir the mixture overnight. Quenchthe reaction with 1.0 N NaOH (4.0 mL) and take up the mixture in Et₂O(30 mL). Separate the layers, and extract the aqueous layer with Et₂O(3×20 mL). Wash the organic layers with brine (40 mL), dry over MgSO₄,and concentrate. Purify by flash chromatography, eluting with 55:40:5EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH to afford a diasteremeric mixture of theproduct (144.7 mg, 65%), which is separable by repeated flashchromatography, eluting with 5-10% 2.0 M NH₃ in MeOH/CH₂Cl₂: MS ES⁺470.1 (M+H)⁺, ES⁻ 468.2 (M−H)⁻.

Part D:(±)-(cis)-6-{4-[2-(3-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Treat(±)-(cis)-6-(4-{2-[3-(tert-butyldimethyl-silyloxy)cyclohexylamino]ethyl}phenoxy)nicotinamide(56.8 mg, 0.12 mmol) in THF (1.0 mL) with 1.0 M tetrabutylammoniumfluoride (TBAF) in THF (0.5 eq) for 1 hour. Add another 0.5 eq of 1.0 MTBAF and stir for 4 hours. Add 1.0 eq of 1.0 M TBAF and stir for 2.5days. Concentrate and purify by flash chromatography, eluting with 10%(2.0 M NH₃ in MeOH) in CH₂Cl₂. Repeat the chromatography to afford thetitle compound (29.9 mg, 70%): MS ES⁺ 356.0 (M+H)⁺, HRMS calcd forC₂₁H₂₈N₃O₂ 356.1974 (M+H)⁺, found 356.1965, time 0.41 min; HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in0.1% TFA/water at 1.0 mL/min, 5-99% over 19 min], t_(R)=7.11 min, 100%purity; Anal. Calcd for C₂₀H₂₅N₃O₃.0.4CH₂Cl₂.0.4MeOH: C, 62.11; H, 6.87;N, 10.45. Found: C, 61.95; H, 6.88; N, 10.36.

EXAMPLE 452(±)-(trans)-6-{4-[2-(3-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Treat(±)-(trans)-6-(4-{2-[3-(tert-butyldimethyl-silyloxy)cyclohexylamino]ethyl}phenoxy)nicotinamide(Example 451, Part C, 63.3 mg, 0.13 mmol) in THF (1.0 mL) with 1:0 Mtetrabutylammonium fluoride (TBAF) in THF (0.5 eq) for 1 hour. Addanother 0.5 eq of 1.0 M TBAF and stir for 4 hours. Add 1.0 eq of 1.0 MTBAF and stir for 9 days. Add another 1.0 eq of 1.0 M TBAF and stir for4 days. Concentrate, dissolve the mixture in CH₂Cl₂ (20 mL), and washwith H₂O (2×20 mL), saturated aqueous NaHCO₃ and brine (20 mL each).Back-extract the aqueous layers with CH₂Cl₂ (20 mL). Concentrate the twoH₂O washings and purify by flash chromatography, eluting with 15% (2.0 MNH₃ in MeOH) in CH₂Cl₂ to afford the title compound (42.1 mg, 88%): MSES⁺ 356.4 (M+H)⁺, HRMS calcd for C₂₁H₂₈N₃O₂ 356.1974 (M+H)⁺, found356.1979, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-99%over 19 min], t_(R)=7.11 min, 100% purity.

EXAMPLE 453(±)-6-{4-[2-((trans)-4-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Part A: (±)-(trans)-4-[2-(4-Methoxyphenyl)ethylamino]cyclohexanol

Heat a mixture of (±)-(trans)-4-aminocyclohexanol (607 m, 5.3 mmol),Cs₂CO₃ (4.300 g, 13.2 mmol), and 1-(2-chloroethyl)-4-methoxybenzene (0.8mL) in DMF (10 mL) at 100° C. for 19 hours. Quench the reaction withsaturated aqueous NH₄Cl (40 mL). Adjust the pH to alkaline andconcentrate to dryness. Suspend the residue in 50:40:10 EtOAc/CH₂Cl₂/2.0M NH₃ in MeOH and stir vigorously for 1 hour. Decant the supernatant.Suspend the residue in 10:90 2.0 M NH₃ in MeOH/CH₂Cl₂ for 30 minutes andfilter. Combine the organic layers, concentrate, and purify by flashchromatography, eluting with 75:15:10 EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH toafford the title compound (258.3 mg, 20%): MS ES⁺ 250.0 (M+H)⁺, HPLC[YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min],t_(R)=1.96 min, 100% purity.

Part B:(±)-6-{4-[2-((trans)-4-Hydroxycyclohexylamino)ethyl]phenoxy}nicotinamide

Add dropwise 1.0 M BBr₃ in heptane (1.35 mL, 1.35 mmol) to a suspensionof (±)-(trans)-4-[2-(4-methoxyphenyl)ethylamino]cyclohexanol (Part A,153.2 mg, 0.61 mmol) in anhydrous CH₂Cl₂ (5.0 mL) at 0° C. Add another1.0 mL of CH₂Cl₂ when the compound precipitates out. Stir the mixture at0° C. for 30 minutes and at room temperature for 2 hours. Quench thereaction with 5 drops of H₂O and concentrate. Purify the residue on anSCX column, washing with MeOH and then eluting with 2.0 M NH₃ in MeOH toyield (±)-(tans)-4-[2-(4-hydroxycyclohexylamino)ethyl]phenol (121.2 mg).

Heat a mixture of the phenol (121.2 mg, 0.52 mmol), 6-chloronicotinamide(121.0 mg, 0.77 mmol), and K₂CO₃ (213.5 mg, 1.55 mmol) in 3:1DMF/toluene (6.0 mL) at 165° C. for 3 hours. Quench the reaction with asmall amount of H₂O and concentrate to dryness, using xylenes to removeDMF azeotropically. Dissolve the residue in MeOH and filter. Concentratethe filtrate and purify by flash chromatography, eluting with 75:15:10EtOAc/CH₂Cl₂/2.0 M NH₃ in MeOH, to afford the title compound (79.1 mg,43%): MS ES⁺ 356.0 (M+H)⁺, HRMS calcd for C₂₀H₂₆N₃O₃ 356.1974 (M+H)⁺,found 356.1959, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 5-95% over 19 min], t_(R)=5.81 min, 100% purity.

EXAMPLE 454(±)-6-{4-[2-((trans)-2-Hydroxycyclopentylamino)ethyl]phenoxy}nicotinamide

Part A: 4-[2-(2-Hydroxycyclopentylamino)ethyl]phenol

Stir a mixture of cyclopentene oxide (482.0 mg, 5.73 mmol) and tyramine(943.2 mg, 6.88 mmol) in 1.0 N NaOH (20 mL) at room temperature for 64hours, at 45-55° C. for 6 hours, and at 100° C. for 18 hours. Quench thereaction with saturated aqueous NH₄Cl (40 mL) and take it up in EtOAc(50 mL). Separate the layers after shaking. Wash the organic layer withH₂O and brine (50 mL each). Back-extract the aqueous layers with CH₂Cl₂,EtOAc and CH₂Cl₂ (50 mL each). Adjust the pH of the combined aqueouslayers to alkaline and concentrate. Suspend the residue in 10:40:50 2.0M NH₃ in MeOH/CH₂Cl₂/EtOAc and decant off the supernatant. Dissolve theresidual solid in H₂O and extract it with 10:40:50 2.0 M NH₃ inMeOH/CH₂Cl₂/EtOAc (100 mL) and 10:90 2.0 M NH₃ in MeOH/CH₂Cl₂. Combineall the organic layers and concentrate. Dissolve the residue in a smallamount of MeOH and purify by flash chromatography, eluting with 10:40:502.0 M NH₃ in MeOH/CH₂CL₂/EtOAc to afford the title compound as a 1:3cis/trans isomeric mixture (566 mg, 45%): MS ES⁺ 222.0 (M+H)⁺, HPLC[YMC-Pack Pro C-18 (150×4.6 min, S-5 microm), acetonitrile in watercontaining 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min],t_(R)=4.72 min, 76% and 6.52 min, 24%.

Part B:(±)-6-{4-[2-((trans)-2-Hydroxycyclopentylamino)ethyl]phenoxy}nicotinamide

Heat a mixture of 4-[2-(2-hydroxycyclopentylamino)ethyl]phenol (210.5mg, 0.95 mmol), K₂CO₃ (395 mg, 2.85 mmol) and 6-chloronicotinamide(223.4 mg, 1.43 mmol) in 1:3 toluene/DMF (6 mL) at 165° C. for 2 hours,while removing H₂O azeotropically with toluene. Remove DMFazeotropically with xylenes and take up the residue in H₂O (50 mL) and10% MeOH in CH₂Cl₂ (50 mL). Shake and separate the layers. Extract theaqueous layer with 10% MeOH in CH₂Cl₂ (2×50 mL) and 10% MeOH in EtOAc(50 mL). Combine the organic layers, dry over MgSO₄ and concentrate.Concentrate the aqueous layer, which still contains the product by TLC,to dryness and extract the product out with MeOH. Dry the solution withNa₂SO₄, filter and combine with the organic concentrate above.Concentrate, re-dissolve in MeOH and filter through a Na₂SO₄ pad.Concentrate and purify by flash chromatography, eluting with 10:15:752.0 M NH₃ in MeOH/CH₂CL₂/EtOAc to afford the title compound (137.4 mg)along with the (cis)-isomer of the starting phenol (59.0 mg) recovered:MS ES+342.0 (M+H)⁺, HRMS calcd for C₁₉H₂₄N₃O₃ 342.1818 (M+H)⁺, found342.1812, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 5-95% over 19 min], t_(R)=16.76 min, 100% purity; Anal. Calcdfor C₁₉H₂₃N₃O₃.0.1CH₂Cl₂.0.1 EtOAc: C, 65.29; H, 6.74; N, 11.71. Found:65.35; H, 6.61; N, 11.98.

EXAMPLE 455 4-[5-(Phenethylamino-methyl)-pyridin-2-yloxy]-benzamidedihydrochloride

Step 1 4-(5-Cyano-pyridin-2-yloxy)-benzamide

Combine 6-chloro-nicotinonitrile (1.0 g, 7.22 mmol), 4-hydroxybenzamide(1.09 g, 7.94 mmol), and potassium carbonate (1.49 g, 10.83 mmol) intoluene (8 mL). Add DMA (24 mL) to the reaction mixture. Heat thereaction mixture for 1.5 hour at 120° C. Let the reaction mixture coolto room temperature. Pour the reaction mixture onto water and filter theprecipitate washing with water. Dry the solid under vacuum to providethe title compound (1.63 g, 94%)

Step 2 4-(5-Aminomethyl-pyridin-2-yloxy)-benzamide

Combine 4-(5-cyano-pyridin-2-yloxy)-benzamide (202 mg, 0.844 mmol), 5%Pd/C (80 mg) and conc. HCl (0.423 mL) in THF (4 mL) and EtOH (4 mL). Runthe reaction under hydrogen atmosphere (1 atm) at rt overnight. Add NaOH(5 N, 2 mL) and filter the reaction mixture through Celite®. Concentratethe filtrate. Wash the residue with H₂O (5 mL) and extract with CH₂Cl₂(3×5 mL). Combine the organic layers and purify through an SCX columneluting with 2M ammonia in methanol. Concentrate the fractions to givethe title compound (74 mg, 36%).

Step 3

Combine 4-(5-aminomethyl-pyridin-2-yloxy)-benzamide (70 mg, 0.288 mmol)from step 2, methanol (1.8 mL), trimethylorthoformate (1.2 mL), andphenethyl aldehyde (0.034 mL, 0.288 mL). Stir at room temperature for 4hours, then add sodium borohydride (13 mg, 0.346 mmol). Stir for 4 h.Purify through an SCX column using ammonia (2.0 M in methanol) to give20 mg (20%) of the free base. Combine the compound with ether (1 mL) andhydrochloric acid (1 M in ether). Triturate and filtrate to give 24 mgof the title compound. Mass spectrum (ion spray): m/z=348.0 (M+1); ¹HNMR (CDCl₃): 8.02 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.6 Hz, 2H), 7.62 (dd,J=2.1 Hz, 8.6 Hz, 1H), 7.25-7.19 (m, 2H), 7.16-7.08 (m, 5H), 6.85 (d,J=8.3 Hz, 1H), 6.18-5.72 (bm, 2H), 3.69 (s, 2H), 2.83 (t, J=6.4 Hz, 2H),2.75 (t, J=6.4 Hz, 2H), 1.85-1.51 (bs, 1H).

EXAMPLE 4564-{5-[(3-Trifluoromethyl-benzylamino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to Example 455, step 3, using3-trifluoro-benzaldehyde (0.045 mL, 0.339 mmol) gives the title compound(106 mg, 85%). Mass spectrum (ion spray): m/z=401.9 (M+1); ¹H NMR(DMSO-d₆): 8.08 (d, J=2.4 Hz, 1H), 7.97-7.93 (bs, 1H), 7.90 (d, J=8.7Hz, 2H), 7.85 (dd, J=2.4 Hz, 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J=7.6Hz, 1H), 7.58-7.50 (m, 2H), 7.33 (s, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.03(d, J=8.5 Hz, 1H), 3.76 (s, 2H), 3.66 (s, 2H).

EXAMPLE 4574-{5-[(3-Phenyl-propylamino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to Example 455, step 3, using3-phenyl-propyl-aldehyde (0.045 mL, 0.339 mmol) gives the title compound(45 mg, 41%). Mass spectrum (ion spray): m/z=361.9 (M+1); ¹H NMR(DMSO-d₆): 8.07 (d, J=2.1 Hz, 1H), 7.94 (bs, 1H), 7.90 (d, J=8.7 Hz,2H), 7.82 (dd, J=2.5 Hz, 8.3 Hz, 1H), 7.33 (bs, 1H), 7.24 (t, J=7.4 Hz,2H), 7.17-7.11 (m, 5H), 7.02 (d, J=8.3 Hz, 1H), 3.64 (s, 2H), 2.58 (t,J=7.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 1.69 (quintet, J=7.6 Hz, 2H).

EXAMPLE 4584-{5-[(4-Fluoro-benzylamino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to Example 455, step 3, using4-fluoro-benzaldehyde (0.036 mL, 0.339 mmol) gives the title compound(97 mg, 90%). Mass spectrum (ion spray): m/z=351.9 (M+1); ¹H NMR(DMSO-d₆): 8.07 (d, J=2.3 Hz, 1H), 7.95 (bs, 1H), 7.90 (d, J=9.0 Hz,2H), 7.84 (dd, J=2.5 Hz, 8.4 Hz, 1H), 7.37-7.32 (m, 3H), 7.14-7.08 (m,4H), 7.03 (d, J=8.6 Hz, 1H), 3.64 (s, 2H), 3.63 (s, 2H).

EXAMPLE 459 4-[5-(Isobutylamino-methyl)-pyridin-2-yloxy]-benzamide

Using a method similar to Example 455, step 3, using isobutylaldehyde(0.031 mL, 0.339 mmol) gives the title compound (71 mg, 77%). Massspectrum (ion spray): m/z=300.0 (M+1); ¹H NMR (DMSO-d₆): 8.07 (d, J=2.4Hz, 1H), 7.94 (bs, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.82 (dd, J=2.4 Hz, 8.2Hz, 1H), 7.32 (bs, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.2 Hz, 1H),3.64 (s, 2H), 2.26 (d, J=6.6 Hz, 2H), 1.64 (septet, J=6.6 Hz, 1H), 0.84(d, J=6.6 Hz, 6H).

EXAMPLE 460 4-{5-[(3,3-Dimethyl-butylamino)-methyl]-pyridin-2-yloxy}-

Using a method similar to Example 455, step 3, using3,3-dimethyl-butyraldehyde (0.062 mL, 0.493 mmol) gives the titlecompound (111 mg, 82%). Mass spectrum (ion spray): m/z=327.9 (M+1); ¹HNMR (DMSO-d₆): 8.06 (d, J=2.5 Hz, 1H), 7.93 (bs, 1H), 7.88 (d, J=8.5 Hz,2H), 7.81 (dd, J=2.5 Hz, 8.5 Hz, 1H), 7.31 (bs, 1H), 7.11 (d, J=8.5 Hz,2H), 7.02 (d, J=8.5 Hz, 1H), 3.63 (s, 2H), 2.46 (t, J=8.7 Hz, 2H), 1.98(bs, 1H), 1.33 (t, J=8.7 Hz, 2H), 0.84 (s, 9H).

EXAMPLE 4614-{5-[(3-Methyl-butylamino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to Example 455, step 3, using3-methyl-butyraldehyde (0.053 mL, 0.493 mmol) gives the title compound(102 mg, 79%). Mass spectrum (ion spray): m/z=313.9 (M+1); ¹H NMR(DMSO-d₆): 8.06 (d, J=2.5 Hz, 1H), 7.93 (bs, 1H), 7.88 (d, J=8.7 Hz,2H), 7.81 (dd, J=2.5 Hz, 8.4Hz, 1H), 7.31 (bs, 1H), 7.11 (d, J=8.7 Hz,2H), 7.02 (d, J=8.4 Hz, 1H), 3.63 (s, 2H), 2.45 (t, J=7.3 Hz, 2H), 2.02(bs, 1H), 1.59 (septet, J=6.7 Hz, 1H), 1.28 (q, J=6.9 Hz, 2H), 0.82 (d,J=6.7 Hz, 6H).

EXAMPLE 4624-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamide

Step 1 4-(5-Formyl-pyridin-2-yloxy)-benzamide

Combine 4-(5-cyano-pyridin-2-yloxy)-benzamide (501 mg, 2.09 mmol) inCH₂Cl₂ (10 mL) at 0° C. with DIBAL-H (1.0 M in hexanes, 4.2 mL)dropwise. Stir the reaction mixture for 5 h. Pour the reaction mixtureonto aqueous NH₄Cl and let stir overnight. Filter and redissolve inCHCl₃/iPrOH (3:1, 10 mL) and wash with NaOH (1 N, 7 mL). Extract theorganic layer, dry over magnesium sulfate, filter and dry under vacuumto provide 4-(5-formyl-pyridin-2-yloxy)-benzamide (312 mg, 62%).

Step 2

Using a method similar to Example 455, step 3, using2-thiophen-2-yl-ethylamine (0.027 mL, 0.227 mmol) and4-(5-formyl-pyridin-2-yloxy)-benzamide (58 mg, 0.239 mmol) from step 1(above) gives the title compound (23 mg, 27%). Mass spectrum (ionspray): m/z=353.9 (M+1); ¹H NMR (DMSO-d₆): 8.08 (d, J=2.1 Hz, 1H), 7.93(bs, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.82 (dd, J=2.3 Hz, 8.3 Hz, 1H), 7.31(bs, 1H), 7.27 (dd, J=1.0 Hz, 5.2 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.02(d, J=8.3 Hz, 1H), 6.90 (dd, J=3.5 Hz, 5.2 Hz, 1H), 6.84 (d, J=3.3 Hz,1H), 3.68 (S, 2H), 2.91 (t, J=7.1 Hz, 2H) 2.72 (t, J=7.1 Hz, 2H), 2.25(bs, N—H).

EXAMPLE 4634-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide

Using a method similar to example 462, step 2, using3-fluoro-phenyl)-ethylamine (0.026 mL, 0.2 mmol) gives the titlecompound (14 mg, 18%) Mass spectrum (ion spray): m/z=365.9 (M+1); ¹H NMR(DMSO-d₆): 8.06 (bs, 1H), 7.93 (bs, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.79(d, J=8.2 Hz, 1H), 7.32-7.24 (m, 2H), 7.11 (d, J=8.2 Hz, 2H), 7.05-6.93(m, 5H), 3.67 (s, 2H), 2.76-2.64 (m, 4H).

EXAMPLE 4644-(5-{[2-(2-Methoxy-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide

Using a method similar to example 462, step 2, using2-methoxy-phenyl-ethylamine (0.033 mL, 0.223 mmol) gives the titlecompound (48 mg, 57%). Mass spectrum (ion spray): m/z=377.9 (M+1); ¹HNMR (DMSO-d₆): 8.06 (d, J=2.1 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.6 Hz,2H), 7.79 (dd, J=2.4 Hz, 8.2 Hz, 1H), 7.31 (bs, 1H), 7.17-7.09 (m, 4H),7.01 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H),3.73 (s, 3H), 3.66 (s, 2H), 2.71-2.60 (m, 4H), 2.16 (bs, N—H).

EXAMPLE 4654-(5-{[2-(2-Chloro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide

Using a method similar to example 462, step 2, using2-chloro-phenyl)-ethylamine (0.028 mL, 0.198 mmol) gives the titlecompound (42 mg, 55%). Mass spectrum (ion spray): m/z=381.8 (M+1); ¹HNMR (DMSO-d₆) 8.06 (bs, 1H), 7.93 (bs, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.80(d, J=8.3 Hz, 1H), 7.40-7.29 (m, 3H), 7.26-7.17 (m, 2H), 7.11 (d, J=8.3Hz, 2H), 7.01 (d, J=8.3 Hz, 1H), 3.68 (s, 2H), 2.82 (t, J=6.6 Hz, 2H),2.68 (t, J=6.6 Hz, 2H), 2.27 (bs, N—H).

EXAMPLE 466(±)-4-[5-(3-Phenyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxy]-benzamide

Step 1 4-(5-Formyl-pyridin-2-yloxy)-benzamide

Combine 4-(5-cyano-pyridin-2-yloxy)-benzamide (501 mg, 2.09 mmol) inCH₂Cl₂ (10 mL) at 0° C. with DIBAL-H (1.0 M in hexanes, 4.2 mL)dropwise. Stir the reaction mixture for 5 h. Pour the reaction mixtureonto aqueous NH₄Cl and let stir overnight. Filter and redissolve inCHCl₃/iPrOH (3:1, 10 mL) and wash with NaOH (1 N, 7 mL). Extract theorganic layer, dry over magnesium sulfate, filter and dry under vacuumto provide 4-(5-formyl-pyridin-2-yloxy)-benzamide (312 mg, 62%).

Step 2

Combine 4-(5-formyl-pyridin-2-yloxy)-benzamide (100 mg, 0.413 mmol),(±)-3-phenyl-pyrrolidine (78 mg, 0.318 mmol), sodiumtriacetoxy-borohydride (101 mg, 0.477 mmol), AcOH (0.018 mL, 0.318 mmol)in CH₂Cl₂ (5 mL). Stir at rt overnight. Pour the reaction mixture ontoan SCX column, eluting with ammonia (2M in methanol) followed bychromatography [CH₂Cl₂:ammonia (2.0 M in methanol) 20:1] to provide thetitle compound (43 mg, 36%). Mass spectrum (ion spray): m/z=373.9 (M+1);¹H NMR (DMSO-d₆): 8.09 (d, J=1.9 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.6Hz, 2H), 7.82 (dd, J=2.2 Hz, 8.6 Hz, 1H), 7.30 (bs, 1H), 7.27-7.24 (m,4H), 7.17-7.12 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 3.61 (dd, J=13.1 Hz,19.5 Hz, 2H), 3.33-3.24 (m, 1H), 2.88 (t, J=8.3 Hz, 1H), 2.66 (t, J=7.0Hz, 2H), 2.42 (t, J=8.3 Hz, 1H), 2.28-2.18 (m, 1H), 1.79-1.70 (m, 1H).

EXAMPLE 4674-{5-[(3,3-Dimethyl-butylamino)-methyl]-pyridin-2-yloxy}-benzamide

The title compound is prepared following the procedure of Example 462using the corresponding amine. Mass spectrum (ion spray): m/z=327.9(M+l); ¹H NMR (DMSO-d₆): 8.06 (d, J=2.5 Hz, 1H), 7.93 (bs, 1H), 7.88 (d,J=8.5 Hz, 2H), 7.81 (dd, J=2.5 Hz, 8.5 Hz, 1H), 7.31 (bs, 1H), 7.11 (d,J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 1H), 3.63 (s, 2H), 2.46 (t, J=8.7 Hz,2H), 1.98 (bs, 1H), 1.33 (t, J=8.7 Hz, 2H), 0.84 (s, 9H).

EXAMPLE 4684-{5-[(3-Methyl-butylamino)-methyl]-pyridin-2-yloxy}-benzamide

The title compound is prepared following the method of Example 455, step3 using the corresponding amine. Mass spectrum (ion spray): m/z=313.9(M+1); ¹H NMR (DMSO-d₆): 8.06 (d, J=2.5 Hz, 1H), 7.93 (bs, 1H), 7.88 (d,J=8.7 Hz, 2H), 7.81 (dd, J=2.5 Hz, 8.4 Hz, 1H), 7.31 (bs, 1H), 7.11 (d,J=8.7 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H), 3.63 (s, 2H), 2.45 (t, J=7.3 Hz,2H), 2.02 (bs, 1H), 1.59 (septet, J=6.7 Hz, 1H), 1.28 (q, J=6.9 Hz, 2H),0.82 (d, J=6.7 Hz, 6H).

EXAMPLE 4694-{3-Chloro-5-[(2-thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamide

Step 1 5,6-Dichloro-pyridine-3-carbaldehyde

Combine (5,6-dichloro-pyridin-3-yl)-methanol (3.05 g, 17.11 mmol) andmanganese dioxide (37.2 g, 427.9 mmol) in CH₂Cl₂ (25 mL). Stir thereaction mixture at rt overnight. Filter the reaction mixture throughCelite® washing with CH₂Cl₂ (2×10 mL). Concentrate the filtrate and dryunder vacuum to provide the title compound (1.44 g, 48%).

Step 2 4-(3-Chloro-5-formyl-pyridin-2-yloxy)-benzamide

Combine 5,6-dichloro-pyridine-3-carbaldehyde (1.37 g, 7.80 mmol),4-hydroxy-benzamide (1.18 g, 8.58 mmol), potassium carbonate (1.62 g,11.7 mmol) in toluene (10 mL) and DMA (30 mL). Stir the reaction mixtureat 100° C. for 1 h. Pour the reaction mixture onto H₂O (100 mL) andextract with Et₂O (100 mL). Wash the organic layer with H₂O (2×100 mL),dry the organic phase extracts over magnesium sulfate, filter andconcentrate to give the title compound (1.09 g, 51%).

Step 3

Using a method similar to Example 460, using4-(3-chloro-5-formyl-pyridin-2-yloxy)-benzamide (114 mg, 0.412 mmol) and2-thiophen-2-yl-ethylamine (0.048 mL, 0.412 mmol) gives the titlecompound (57 mg, 36%). Mass spectrum (ion spray): m/z=387.9 (M+1); ¹HNMR (DMSO-d₆): 8.37 (bs, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.99 (bs, 1H),7.93 (d, J=8.7 Hz, 2H), 7.39 (dd, J=1.2 Hz, 5.0 Hz, 1H), 7.36 (bs, 1H),7.21 (d, J=8.9 Hz, 2H), 6.99-6.94 (m, 2H), 4.16 (s, 2H), 3.26-3.11 (m,4H).

EXAMPLE 4704-(3-Chloro-5-{[2-(3-chloro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamide

Using a method similar to Example 462, using4-(3-chloro-5-formyl-pyridin-2-yloxy)-benzamide (101 mg, 0.365 mmol) and2-(3-chloro-phenyl)-ethylamine (0.056 mL, 0.402 mmol) gives the titlecompound (57 mg, 36%). Mass spectrum (ion spray): m/z=415.9 (M+1); ¹HNMR (CDCl₃): 7.93 (d, J=1.7 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.77 (d,J=1.7 Hz, 1H), 7.22-7.17 (m, 4H), 7.07 (d, J=7.0 Hz, 1H), 6.12 (bs, 2H),3.74 (s, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 1.42 (bs,1H).

General Procedure for Examples 471-474

To a mixture of amine (1 equiv), aldehyde (1.5 equiv) in 5%AcOH/methanol (0.2 M) was added NaCNBH₄ (5 equiv) and the resultingreaction mixture was stirred for 2 hours under nitrogen atmosphere atroom temperature. The reaction can be monitored by electrospray MS orTLC. Ethyl actetate was added to the reaction mixture and washed twicewith saturated aqueous solution of NaHCO₃. The organic layer wasseparated, dried over anhydrous NaSO₄ and the solvent was evaporated toyield a residue which was purified by flash chromatography usingchloroform/ethanol/NH₄OH, 94.5/5/0.5) to afford the title compound as awhite solid.

EXAMPLE 4716-[2-Fluoro-4-((3-methyl-butyl)pentylaminomethyl)phenoxy]nicotinamide

Reductive amination of N-pentyl-N-3-methylbutylamine and6-(2-fluoro-4-formyl-phenoxy)-nicotinamide as described above affordedthe title compound in 86% yield.

¹H NMR (CHCl₃-d₃) δ: 8.56 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=8.5, 2.4Hz), 7.28-7.10 (m, 3H), 7.02 (d, 1H, J=8.7 Hz), 6.21 (bs, 2H), 3.54 (s,2H), 2.42 (dt, 4H, J=8.7 Hz), 1.65-1.53 (m, 1H), 1.53-1.40 (m, 2H),1.40-1.20 (m, 6H), 0.86 (t, 3H, J=7.0 Hz), 0.85 (d, 6H, J=6.5 Hz). ¹³CNMR (CHCl₃-d₃) δ: 167.6, 165.5, 156.4, 153.1, 147.4, 139.7, 124.8,123.5, 117.3, 117.1, 111.0, 58.2, 54.2, 52.3, 36.3, 30.0, 27.0, 26.6,23.1, 23.0, 14.5. MS (Electrospray): 402.2 (M⁺+1).

EXAMPLE 4726-[2-Fluoro-4-((3-methyl-butylpropylamino)methyl)phenoxy]nicotinonamide

The title compound was prepared by reductive amination of6-[2-fluoro-4-((3-methyl-butyl) aminomethyl)phenoxy]nicotinamide withpropanaldehyde in 86% Yield.

¹H NMR (CHCl₃-d₃) δ: 8.56 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=8.5, 2.4Hz), 7.28-7.10 (m, 3H), 7.02 (d, 1H, J=8.5 Hz), 6.24 (bs, 2H), 3.54 (s,2H), 1.65-1.55 (m, 1H), 1.55-1.40 (m, 2H), 1.40-1.30 (m, 2H), 0.86 (t,3H, J=7.0 Hz), 0.85 (d, 6H, J=6.5 Hz). ¹³C NMR (CHCl₃-d₃) δ: 167.6,165.5, 156.4, 153.1, 147.5, 139.7, 124.8, 123.5, 117.3, 117.1, 111.0,58.2, 56.3, 52.3, 36.3, 26.6, 23.1, 20.6, 12.3. MS (Electrospray): 374.2(M⁺+1).

EXAMPLE 4736-[4-Bis-((3-methyl-butylamino)-methyl)-2-fluorophenoxy]nicotinonamide

The title compound was prepared by reductive amination of6-[2-fluoro-4-((3-methyl-butyl) aminomethyl)phenoxy]nicotinamide with3-methylbutanaldehyde in 80% Yield. ¹H NMR (CHCl₃-d₃) δ: 8.55 (d, 1H,J=2.4 Hz), 8.17 (dd, 1H, J=8.5, 2.4 Hz), 7.28-7.10 (m, 3H), 7.02 (d, 1H,J=8.7 Hz); 6.25 (bs, 2H), 3.53 (s, 2H), 2.44 (t, 4H, J=7.3 Hz), 1.58(sept, 2H, J=7.3 Hz), 1.35 (dt, 4H, J=7.3 Hz), 0.85 (dd, 6H, J=6.7 Hz).¹³C NMR (CHCl₃-d₃) δ: 167.6, 165.5, 156.4, 153.1, 147.5, 139.7, 124.8,123.5, 117.4, 117.1, 111.0, 58.2, 52.3, 36.3, 26.6, 23.1. MS(Electrospray): 402.2 (M⁺+1).

EXAMPLE 4746-[4-1-(2-Thiophen-2-ylethylaminoethyl)-phenoxy]nicotinonamide

Step 1 (4-Acetyl-phenoxy)nicotinamide

4-Hydroxyacetophenone (1 equiv), 6-chloronicotinamide (1 equiv) andK₂CO₃ (1.4 equiv) in anhydrous DMF (0.4 M) was heated at 150° C. undernitrogen during 2.5 days. After cooling down to room temperature,toluene was added and solvents were evaporated. The residue waspartitioned in water/EtOAc. The aqueous layer was thoroughly extractedwith EtOAc. The combined organic layer was dried over Na₂SO₄, filteredand concentrated under vacuum (toluene was added to aid DMFevaporation). The crude mixture was purified by flash chromatographyusing EtOAc/CH₂Cl₂/2 M NH₃ in MeOH (12:7:1) as eluent in 20% yield.

¹H NMR (MeOH-d₄) δ: 8.63 (d, 1H, J=2.7 Hz), 8.30 (dd, 1H, J=8.6, 2.7Hz), 8.06 and 7.25 (AA′BB′ system, 4H), 7.10 (d, 1H, J=8.6 Hz), 2.61 (s,3H) ¹³C NMR (MeOH-d₄) δ: 196.2, 165.1, 163.4, 156.8, 146.9, 139.2,132.9, 129.7, 125.3, 120.6, 110.8, 26.1 MS (Electrospray): 257.0 (M⁺+1).

Step 2

To a mixture of the ketone (step 1) (1 equiv) and2-thiophen-2-ylethylamine (1.5 equiv), in THF (0.04 M) was addedtitanium tetraisopropoxide (2 equiv) at 0° C. and the resulting solutionwas stirred overnight under nitrogen atmosphere at room temperature. Thefollowing day titanium tetrachloride (1.0 M solution in CH₂Cl₂, 2 equiv)was added and the reaction mixture was stirred for 2.5 hours. NaCNBH₄was added (2 equiv) and stirring was kept for 2 more hours. The reactioncan be monitored by electrospray MS. The reaction mixture was quenchedwith saturated solution of NaHCO₃, and diluted with EtOAc. The reactionmixture was filtered off and the filtrate was evaporated to yield aresidue which was purified by SCX. Quantitative yield.

¹H NMR (MeOH-d₄) δ: 8.61 (d, 1H, J=2.4 Hz), 8.23 (dd, 1H, J=8.7, 2.4Hz), 7.40-7.30 (m, 2H), 7.20-7.05 (m, 3H), 7.00-6.75 (m, 3H), 3.82 (q,1H, J=7.5 Hz), 2.95 (m, 2H), 2.70 (m, 2H), 1.34 (d, 3H, J=7.5 Hz). ¹³CNMR (MeOH-d₄) δ: 167.2, 164.7, 151.6, 146.4, 146.3, 140.9, 138.4, 126.9,125.5, 123.7, 122.1, 120.0, 109.5, 56.2, 36.0, 28.3, 21.4. MS(Electrospray): 368.2 (M⁺+1).

Intermediates for Examples 475-480 Intermediate 1

3-Chloro-4-hydroxybenzaldehyde (2 g, 12.8 mmol), nitromethane (4.68 g,76.6 mmol) and ammonium acetate (3.93 g, 51.1 mmol) are dissolved in 20mL acetic acid and the reaction mixture is heated at 110° C. After 3.5 hthe reaction mixture is concentrated under reduced pressure and theresidue is partitioned between EtOAc and water. Separate the layers andwash the organic layer with brine. Dry with sodium sulfate, filter andconcentrate under reduced pressure. Silica gel chromatography usinghexanes: dichloromethane: EtOAc in a 60:35:5 ratio afforded 1.26 g (49%)of the title compound.

¹H-NMR (CDCl₃, 400 MHz): 7.90 (d, 1H, J=13.6 Hz), 7.55 (d, 1H, J=1.8Hz), 7.49 (d, 1H, J=13.6 Hz), 7.41 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.3Hz), 5.92 (s, 1H),

Intermediate 2

To a solution of lithium aluminum hydride (0.325 g, 8.55 mmol) in 30 mLof THF at 0° C. is added aluminum trichloride (1.14 g, 8.55 mmol). After5 min the intermediate 1 (0.57 g, 2.85 mmol) is added dropwise in 15 mLof THF and the reaction is allowed to stir for 18 h. 100 mL of water and10 mL of 5 N HCl are added and the reaction mixture is extracted with3:1 n-butanol:toluene. The combined organic layers are washed withbrine, dried over sodium sulfate and concentrated. SCX ion-exchangechromatography afforded 335 mg (68%) of the title compound. MS (APCI):(M⁺+1), ¹H-NMR (DMSO, 400 MHz): 7.14 (m, 1H), 6.92 (m, 1H), 6.83 (m,1H), 2.86 (d, 1H, J=7.48, 7.05 Hz), 2.69 (t, 1H, J=7.48, 7.05 Hz), 2.59(d, 1H, J=7.48, 7.05 Hz), 2.50 (d, 1H, J=7.48, 7.05 Hz).

Intermediate 3

To a solution of the intermediate 2 (400 mg, 2.32 mmol) in 15 mL of THFis added di-tert-butyl dicarbonate (557 mg, 2.56 mmol) and sodiumbicarbonate (234 mg, 2.79 mmol) After 18 h the reaction mixture ispartitioned between EtOAc and brine. The organic layer is separated andwashed with 1 M citric acid and brine. It is dried over sodium sulfate,filtered and concentrated. Silica gel chromatography using 5-10% EtOAcin dichloromethane afforded 430 mg (68%) of the title compound. MS(APCI): (M⁺+1-Boc group), ¹H-NMR (CDCl₃, 400 MHz): 7.14 (d, 1H, J=1.5Hz), 6.99 (dd, 1H, J=8.3, 1.9 Hz), 6.94 (d, 1H, J=7.8 Hz), 3.32 (m, 2H),2.70 (t, 2H, J=6.8 Hz), 1.43 (s, 9H).

Intermediate 4

A solution of the intermediate 3 (700 mg, 2.57 mmol),6-chloronicotinonitrile (392 mg, 2.83 mmol) and sodium hydride (113 mg,2.83 mmol) is stirred for 18 h. The reaction mixture is partitionedbetween ethyl acetate and brine. The organic layer is separated, washedwith water and brine, dried over sodium sulfate, filtered andconcentrated. Silica gel chromatography using 0-10% ethyl acetate indichloromethane afforded 895 mg (93%) of the title compound. MS (APCI):(M⁺+1-Boc group) 274, ¹H-NMR (CDCl₃, 400 MHz): 8.42 (d, 1H, J=1.9 Hz),7.94 (dd, 1H, J=8.8, 2.4 Hz), 7.32 (d, 1H, J=1.5 Hz), 7.08-7.25 (m, 3H),4.61 (bs, 1H), 3.39 (m, 2H), 2.81 (t, 2H, J=6.84 Hz), 1.43 (s, 9H).

Intermediate 5

To a solution of the intermediate 4 (875 mg, 2.34 mmol) in DMSO wasadded potassium carbonate (161 mg, 1.17 mmol) followed by addition of30% hydrogen peroxide solution (10 ml) and the reaction was allowed tostir for 18 h. The reaction mixture was partitioned between ethylacetate and brine. The organic layer was washed with water and brinebefore being dried over sodium sulfate, filtered and concentrated toafford 827 mg (90%) of the title compound. ¹H-NMR (CDCl₃, 400 MHz): 8.55(bs, 1H), 8.21 (dd, 1H, J=8.8, 2.4 Hz), 7.32 (bs, 1H), 7.16 (bs, 2H),7.04 (d, 1H, J=8.8 Hz), 4.63 (bs, 1H), 3.39 (m, 2H), 2.81 (t, 2H, J=6.84Hz), 1.44 (s, 9H).

Intermediate 6

A solution of the intermediate 5 (827 mg, 2.11 mmol) in 25% TFA inmethylene chloride was stirred for 18 h. The reaction mixture wasconcentrated under reduced pressure, and purified using SCX ion-exchangechromatography to afford 587 mg (95%) of the title compound. MS (APCI):(M⁺+1) 292. ¹H-NMR (CDCl₃ with MeOH (d-4), 400 MHz): 8.49 (d, 1H, J=2.4Hz), 8.21 (dd, 1H, J=8.3, 2.4 Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (m, 2H),6.96 (d, 1H, J=8.8 Hz), 2.92 (t, 2H, J=6.9 Hz), 2.72 (t, 2H, J=6.8 Hz).

EXAMPLE 475 6-[4-(2-Benzylamino-ethyl)-2-chloro-phenoxy]-nicotinamide

The intermediate 6 (100 mg, 0.342 mmol) and benzaldehyde (435 mg, 0.411mmol) were dissolved in 5 mL of methanol while stirring for 18 h. NaBH₄(29.4 mg, 0.68 mmol) was added and the reaction continued for anadditional 4 h. The NaBH₄ was neutralized with a few drops of aceticacid and the reaction mixture was loaded directly onto a 2 g SCX columnfor purification to afford 103 mg (79%) of the title compound. MS(APCI): (M⁺+1, M⁺+3) 382, 384. ¹H-NMR (CDCl₃, 400 MHz): 8.53 (d, 1H,J=2.44 Hz), 8.19 (dd, 1H, J=8.3, 2.4 Hz), 7.29-7.33 (m, 6H), 7.14-7.16(m, 2H), 7.03 (d, 1H, J=8.3 Hz), 3.83 (s, 2H), 2.92 (m, 2H), 2.83 (m,2H). ** HPLC Purity: 94%, ** HPLC Retention time: 1.745 minutes.

By the method outlined for the synthesis of Example 475, the followingcompounds were prepared.

Example Name Mass NMR/MS/LC/MS 476 6-{2-Chloro-4-[2-(2-methyl- 395(APCI): (M⁺ + 1, M⁺ + 3) 396, 398 benzylamino)-ethyl]- ¹H-NMR (CDCl₃,400 MHz): phenoxy}-nicotinamide 8.53(d, 1H, J=2.44Hz), 8.19(dd, 1H,J=8.3, 2.4Hz), 7.34(d, 1H, J=1.95Hz), 7.26(m, 1H), 7.12-7.18(m, 5H),7.03(d, 1H, J=7.8Hz), 3.80(s, 2H), 2.97(t, 2H, J=6.84Hz), 2.84(t, 2H,J=6.84Hz), 2.32(s, 3H). **HPLC Purity: 94.6% **HPLC Retention time:1.842 min. 477 6-{2-Chloro-4-[2-(2- 449 (APCI): (M⁺ + 1) 450trifluoromethyl-benzylamino)- **HPLC Purity: 80.8%ethyl]-phenoxy}-nicotinamide **HPLC Retention time: 2.197 min. 4786-{2-Chloro-4-[2-(3-fluoro- 399 (APCI): (M⁺ + 1, M⁺ + 3) 400, 402benzylamino)-ethyl]- ¹H-NMR (CDCl₃ with D₄ phenoxy}-nicotinamide MeOH,400 MHz): 8.49(d, 1H, J=2.44Hz), 8.17(dd, 1H, J=8.3, 2.4Hz),6.90-7.25(m, 8H), 3.75(s, 2H), 2.76-2.84(m, 4H). **HPLC Purity: 93.8%**HPLC Retention time: 1.799 min. 479 6-{2-Chloro-4-[2-(3-chloro- 416(APCI): (M⁺, M⁺ + 2) 416, 418 benzylamino)-ethyl]- ¹H-NMR (CDCl₃ with D₄phenoxy}-nicotinamide MeOH, 400 MHz): 8.46(d, 1H, J=1.95Hz), 8.12(dd,1H, J=8.8, 2.4Hz), 7.04-7.22(m, 7H), 6.88(d, 1H, J=8.3Hz), 3.68(s, 2H),2.73-2.78(m, 4H). **HPLC Purity: 93.4% **HPLC Retention time: 1.857 min.480 6-{2-Chloro-4-[2-(3- 449 (APCI):( M⁺ + 1) 450trifluoromethyl-benzylamino)- **HPLC Purity: 81.9%ethyl]-phenoxy}-nicotinamide **HPLC Retention time: 2.275 min. **HPLCconditions:(10/90 to 90/10 ACN/(0.1% TFA in water) Water's Xterra MS C18Column 4.6 mm × 50 mm × 5 micron.

INTERMEDIATES FOR EXAMPLES 481-482 Intermediate 1

3-Chloro-4-hydroxybenzaldehyde (100 mg, 0.64 mmol) and3,3-dimethyl-1-butylamine (56 mg, 0.55 mmol) were dissolved in 2 mLmethanol containing 3 Å molecular sieves. After 18 hours, sodiumborohydride (41 mg, 1.28 mmol) was added and the reaction was continuedfor another 4 h. The reaction was quenched by the addition of a fewdrops of acetic acid and purified by SCX ion-exchange chromatography toafford 50 mg (37.6%) of the title compound. MS (APCI): (M⁺+1) 242,¹H-NMR (CDCl₃, 400 MHz): 7.29 (d, 1H, J=1.95 Hz), 7.10 (dd, 1H, J=8.3,1.95 Hz), 6.87 (d, 1H, J=8.3 Hz), 3.72 (s, 2H), 2.67 (t, 2H, J=8.3 Hz),1.48 (t, 2H, J=8.8 Hz), 0.89 (s, 9H).

Intermediate 2

To a solution of the intermediate 1 (50 mg, 0.2 mmol) in 2 mL of THF wasadded di-tert-butyl dicarbonate (56.5 mg, 0.26 mmol) and sodiumbicarbonate (26 mg, 0.31 mmol). After 18 h the reaction mixture waspartitioned between EtOAc and brine. The organic layer is separated andwashed with 1 M citric acid and brine, after which it was dried oversodium sulfate, filtered and concentrated. Silica gel chromatographyusing 0-5% EtOAc in dichloromethane afforded 34 mg (48%) of the titlecompound. ¹H-NMR (CDCl₃, 400 MHz): 7.21 (s, 1H), 7.04 (m, 1H), 6.96 (d,1H, J=8.3 Hz), 5.52 (s, 1H), 4.31 (bs, 2H), 3.14 (m, 2H), 1.56 (m, 11H),0.85 (s, 9H).

Intermediate 3

A solution of the intermediate 2 (110 mg, 0.32 mmol),6-chloronicotinonitrile (49 mg, 0.35 mmol) and sodium hydride (14.2 mg,0.35 mmol) was stirred for 18 h. The reaction mixture was partitionedbetween ethyl acetate and brine. The organic layer was separated, washedwith water and brine, dried over sodium sulfate, filtered andconcentrated. Silica gel chromatography using 0-5% ethyl acetate in60:40 hexanes: dichloromethane afforded 23 mg (16%) of the titlecompound. MS (APCI): (M⁺+1-Boc group) 344, ¹H-NMR (CDCl₃, 400 MHz): 8.42(dd, 1H, J=2.2, 0.88 Hz), 7.95 (dd, 1H, J=8.37, 2.2 Hz), 7.36 (s, 1H),7.15-7.20 (m, 2H), 7.09 (d, 1H, J=8.8 Hz), 4.40 (bs, 2H), 3.19 (m, 2H),1.48 (bs, 11H), 0.89 (s, 9H).

Intermediate 4

To a solution of the intermediate 3 (244 mg, 0.55 mmol) in 5 mL of DMSOwas added potassium carbonate (38 mg, 0.275 mmol) followed by 30%hydrogen peroxide solution (2 mL) and the reaction was allowed to stirfor 18 h. The reaction mixture was partitioned between ethyl acetate andbrine. The organic layer was washed with water and brine before beingdried over sodium sulfate, filtered and concentrated to afford 218 mg(86%) of the title compound. MS (APCI: (M⁺+1-Boc group) 362.

EXAMPLE 4816-{2-Choloro-4-[(3,3-dimethylbutylamino)-methyl]-phenoxy}-nicotinamide

A solution of the intermediate 4 (218 mg, 0.47 mmol) in 2.5 mL of 20%TFA in methylene chloride was stirred for 18 h. After the reactionmixture was concentrated under reduced pressure, SCX ion-exchangechromatography followed by silica gel chromatography using 5-10% 2 N NH₃methanol in dichloromethane afforded 151 mg (88%) of the title compound.MS (APCI): (M⁺+1) 362, ¹H-NMR (CDCl₃, 400 MHz): 8.53 (d, 1H, J=2.64 Hz),7.95 (dd, 1H, J=8.8, 2.64 Hz), 7.48 (d, 1H, J=2.2 Hz), 7.29 (dd, 1H,J=8.36, 2.2 Hz), 7.16 (d, 1H, J=7.92 Hz), 7.02 (d, 1H, J=9.24 Hz), 5.93(vbs, 2H), 3.80 (s, 2H), 2.67 (m, 2H), 1.45 (m, 2H), 0.91 (s, 9H).Purity: 94.2%, Retention time: 1.802 minutes.

The following compound is also prepared by the method outlined for thesynthesis of the compound of Example 481.

Exam- ple Name Mass NMR/LC/MS 482 6-{2-Chloro-4-[(2- 387 MS (APCI):(M⁺ + 1) 388, thiophen-2-yl- ¹H-NMR (CDCl₃, 400 MHz): ethylamino)-8.51(bs, 1H), 8.19(dd, 1H, J=8.3, methyl]-phenoxy}- 1.95Hz), 7.43(bs,1Hz), nicotinamide 6.81-7.24 7.29(m, 6H), 3.79(s, 2H), 3.03(m, 2H),2.91(m, 2H). Purity: 87.1% Retention time: 1.696 minutes.

EXAMPLE 4833-Bromo-4-{5-[(2-thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamidedihydrochloride

Step 1 6-Chloro-pyridine-3-carbaldehyde

Combine 6-chloro-nicotino-nitrile (1.00 g, 7.21 mmol) and toluene (24mL). Cool the resulting solution at 0° C. and add DIBAL-H (1.0 M intoluene, 7.58 mL, 7.58 mmol) dropwise. Stir the resulting red solutionat 0° C. for 1 h. Then, add methanol (2 mL) followed by H₂SO₄ (aq. 2.0M, 6 mL). Stir for 1 h at rt. Add CHCl₃:isopropanol (3/1, 15 mL) andwash with Rochelle's salt solution (20 mL), followed by NaHCO₃ (20 mL)and brine. Dry the combined organic layers over magnesium sulfate,filter and concentrate. Purify by flash chromatography (EtOAc/hexanes10%) to give the title compound (530 mg, 62%).

Step 2 3-Bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile

Combine 6-chloro-pyridine-3-carbaldehyde (1.00 g, 7.09 mmol),3-bromo-4-hydroxy-benzonitrile (1.48 g, 7.80 mmol) in dimethylacetamide(40 mL). Add potassium carbonate (1.47 g, 10.64 mmol) and stir and heatthe reaction at 130° C. for 2 h. Let cool down the reaction to roomtemperature and poured into water. Filter the precipitate formed,washing with water, to give the title compound (1.55 g, 72%)

Step 3 3-Bromo-4-(5-formyl-pyridin-2-yloxy)-benzamide

Combine 3-bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (1.60 g, 5.28mmol) and potassium carbonate (365 mg, 2.64 mmol) in DMSO (40 mL). Coolthe reaction mixture at 0° C. Add hydrogen peroxide (1.59 mL, 5.28 mmol)dropwise and let the reaction stir at room temperature for 2 h. Pourinto water and triturate to a white solid with stirring. Filter thewhite solid and dry to give (852 mg, 82%) of the title compound.

Step 4

Using a method similar to example 462, using 2-thiophen-2-ylethylamineand 3-bromo-4-(5-formyl-pyridin-2-yloxy)benzamide (step 3) gives thetitle compound (220 mg, 92%). Mass spectrum (ion spray): m/z=433.9(M+1); ¹H NMR (CDCl₃): 8.11 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.2 Hz. 1H),7.76 (td, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.14 (d, J=5.1 Hz, 1H),7.00 (d, J=8.4 Hz, 1H), 6.93 (dd, J=3.2 Hz, 5.1 Hz, 1H), 6.83 (d, J=3.2Hz, 1H), 6.14 (bs, 1H), 5.87 (bs, 1H), 3.77 (s, 2H), 3.04 (t, J=6.7 Hz,2H), 2.93 (t, J=6.7 Hz, 2H).

EXAMPLE 484 3-Bromo-4-(5-pentylaminomethyl-pyridin-2-yloxy)-benzamide

Using a method similar to example 462, using pentylamine and thebenzamide in Example 483, step 3, gives the title compound (158 mg,65%). Mass spectrum (ion spray): m/z=394.0 (M+1); ¹H NMR (CDCl₃): 8.09(d, J=2.2 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.17(d, J=8.6 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.59 (bs, 1H), 6.34 (bs, 1H),3.73 (s, 2H), 2.59 (t, J=6.8 Hz, 2H), 1.52-1.44 (m, 3H), 1.31-1.25 (m,4H), 0.86 (t, J=6.8 Hz, 3H).

EXAMPLE 4853-Bromo-4-{5-[(3,3-dimethyl-butylamino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to example 462, using cyclohexylmethylamine andthe benzamide in Example 483, step 3, gives the title compound (168 mg,66%). Mass spectrum (ion spray): m/z=408.0 (M+1); ¹H NMR (DMSO-d₆): 8.19(s, 1H), 8.07 (bs, 1H), 8.00 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.83 (d,J=8.5 Hz, 1H), 7.48 (bs, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.08 (d, J=8.5 Hz,1H), 3.63 (s, 2H), 2.46 (t, J=7.8 Hz, 2H), 2.04 (bs, 1H), 1.33 (t, J=7.8Hz, 2H), 0.84 (s, 9H).

EXAMPLE 4863-Bromo-4-{5-[(cyclohexylmethyl-amino)-methyl]-pyridin-2-yloxy}-benzamide

Using a method similar to example 462, using cyclohexylmethylamine andthe benzamide in Example 483 step 3, affords the title compound (209 mg,80%). Mass spectrum (ion spray): m/z=418.2 (M+1); ¹H NMR (DMSO-d₆): 8.18(s, 1H), 8.07 (bs, 1H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.48 (bs, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz,1H), 3.62 (s, 2H), 2.28 (d, J=6.5 Hz, 2H), 1.76-1.57 (m, 5H), 1.40-1.30(m, 1H), 1.22-1.06 (m, 3H), 0.88-0.77 (m, 2H).

EXAMPLE 487 3-Methoxy-4-(5-pentylaminomethyl-pyridin-2-yloxy)-benzamide

Step 1 4-(5-Formyl-pyridin-2-yloxy)-3-methoxy-benzonitrile

Using a method similar to example 483 (step 2), using4-hydroxy-3-methoxy-benzonitrile (1.18 g, 7.91 mmol) gives the titlecompound (1.71 g, 94%).

Step 2 4-(5-Formyl-pyridin-2-yloxy)-3-methoxy-benzamide

Using a method similar to example 483 (step 3), using4-(5-formyl-pyridin-2-yloxy)-3-methoxy-benzonitrile (1.71 g, 6.74 mmol)gives the title compound (1.107 g, 60%).

Step 3

Using a method similar to example 462, using pentylamine and thebenzamide in step 2, gives the title compound (174 mg, 69%). Massspectrum (ion spray): m/z=344.3 (M+1); ¹H NMR (CDCl₃): 8.02 (d, J=1.9Hz, 1H), 7.69 (dd, J=2.1 Hz, 8.6 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.32(dd, J=1.7 Hz, 8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.92 (d, J=8.6 Hz,1H), 6.51 (bs, 1H), 6.25 (bs, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 2.58 (t,J=7.6 Hz, 2H), 1.51-1.43 (m, 3H), 1.31-1.24 (m, 4H), 0.86 (t, J=6.6 Hz,3H).

EXAMPLE 4884-{5-[(3,3-Dimethyl-butylamino)-methyl]-pyridin-2-yloxy}-3-methoxy-benzamide

Using a method similar to example 462, using 3,3-dimethylbutylamine andthe benzamide in Example 487, step 2, gives the title compound (170 mg,65%). Mass spectrum (ion spray): m/z=358.3 (M+1); ¹H NMR (DMSO-d₆): 7.98(bs, 1H), 7.95 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.49 (d,J=8.5 Hz, 1H), 7.36 (bs, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz,1H), 3.71 (s, 3H), 3.61 (s, 2H), 2.45 (t, J=8.4 Hz, 2H), 1.32 (t, J=8.4Hz, 2H), 0.84 (s, 9H).

EXAMPLE 4893-Methoxy-4-{5-[(2-thiophen-2-yl-ethylamino)-methyl]-pyridin-2-yloxy}-benzamidedihydrochloride

Using a method similar to example 462, using 2-thiophen-2-ylethylamineand the benzamide in Example 489, step 2, gives the title compound (188mg, 67%). Mass spectrum (ion spray): m/z=384.2 (M+1); ¹H NMR (CDCl₃):8.01 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J=7.9 Hz,1H), 7.13-7.08 (m, 2H), 6.94-6.86 (m, 2H), 6.81 (s, 1H), 6.67 (bs, 1H),6.42 (bs, 1H), 3.79-3.71 (m, 5H), 3.05-2.98 (m, 2H), 2.93-2.86 (m, 2H).

EXAMPLE 4904-{5-[(Cyclohexylmethyl-amino)-methyl]-pyridin-2-yloxy}-3-methoxy-benzamidedihydrochloride

Using a method similar to example 462, using cyclohexylmethylamine andthe benzamide in Example 487, step 2, gives the title compound (179 mg,66%). Mass spectrum (ion spray): m/z=370.3 (M+1); ¹H NMR (CDCl₃): 8.01(d, J=2.0 Hz, 1H), 7.69 (dd, J=2.2 Hz, 8.2 Hz, 1H), 7.53 (d, J=1.8 Hz,1H), 7.32 (dd, J=1.8 Hz, 8.2 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.91 (d,J=8.4 Hz, 1H), 6.52 (bs, 1H), 6.27 (bs, 1H), 3.76 (s, 3H), 3.69 (s, 2H),2.41 (d, J=6.6 Hz, 2H), 1.74-1.60 (m, 5H), 1.46-1.36 (m, 2H), 1.26-1.09(m, 3H), 0.92-0.81 (m, 2H).

EXAMPLE 4913-Chloro-4-(5-{[2-(3-fluoro-phenyl)-ethylamino]-methyl}-pyridin-2-yloxy)-benzamidedihydrochloride

Step 1 3-Chloro-4-(5-formyl-pyridin-2-yloxy)-benzonitrile

Using a method similar to example 483 (step 2), using3-chloro-4-hydroxy-benzonitrile (527 mg, 3.43 mmol) gives the titlecompound (573 mg, 76%).

Step 2 3-Chloro-4-(5-formyl-pyridin-2-yloxy)-benzamide

Using a method similar to example 483 (step 3) using3-chloro-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (573 mg, 2.36 mmol)gives the title compound (404 mg, 62%).

Step 3

Using a method similar to example 462, using fluorophenethylamine andthe benzamide in step 2, gives the title compound (84 mg, 97%). Massspectrum (ion spray): m/z=400.2 (M+1); ¹H NMR (CDCl₃) 8.01 (s, 1H), 7.93(d, J=2.0 Hz, 1H), 7.73-7.68 (m, 2H), 7.24-7.19 (m, 2H), 6.99-6.86 (m,4H), 6.51 (bs, 1H), 6.33 (bs, 1H), 3.74 (s, 2H), 2.87 (t, J=6.6 Hz, 2H),2.79 (t, J=6.6 Hz, 2H).

EXAMPLE 4924-{2-Methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Step 1 4-(4-Formyl-2-methyl-phenoxy)-benzonitrile

Dissolve 3-hydroxy-3-methyl-benzaldehyde (1.02 g, 7.49 mmol) in DMF (10mL), add K₂CO₃ (1.45 g, 10.49 mmol) and 4-fluorobenzonitrile (906 mg,7.49 mmol), heat the mixture at 130° C. overnight. Add water and extractthe aqueous layer with EtOAc. Combine organic layers and dry overNa₂SO₄. Eliminate the solvent and purify by flash chromatography onsilica gel (eluent: EtOAc/hexane 15/85) to give the title compound (920mg, 52%). TLC: R_(f) in EtOAc/hexane 20/80: 0.32. ¹H-NMR (CDCl₃, 200MHz): 9.96 (s, 1H), 7.84-7.61 (m, 4H), 7.05-6.98 (m, 3H), 2.31 (s, 3H).

Step 2 4-(4-Formyl-2-methyl-phenoxy)-benzamide

The compound of step 1 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to formthe amide form nitrile have been described exhaustively elsewhere inthis document.

¹H-NMR (CDCl₃, 200 MHz): 9.94 (s, 1H), 7.87-7.65 (m, 4H), 7.04-6.95 (m,3H), 5.92 (bs, 2H), 2.34 (s, 3H).

Step 3

Combine 3-methyl-butylamine (93 μl, 0.8 mmol), the aldehyde from Example492, step 2 above and 3 A molecular sieves (1.8 g) in methanol (5 mL),stir the mixture at room temperature overnight. Add NaBH₄ (149 mg, 4.0mmol) and stir at room temperature for 3 hours. Filtrate the mixtureover celite and eliminate the solvent. Purify crude mixture by SCXcolumn to obtain the title compound (190 mg, 73%). Electrospray MS M+1ion=327. ¹H-NMR (CDCl₃, 200 MHz): 7.87-7.80 (m, 2H), 7.32-7.20 (m, 2H),6.96-6.85 (m, 3H), 3.76 (s, 2H), 2.68-2.60 (m, 2H), 2.16 (s, 3H),1.69-1.39 (m, 3H), 0.91 (d, 6H, J=7.0 Hz).

EXAMPLE 493 4-[2-Methyl-4-(phenethylamino-methyl)-phenoxy]-benzamide

Compound 2 was prepared from aldehyde described in Example 492, step 2and phenethylamine using the reductive amination conditions describedabove. Electrospray MS M+1 ion=361. ¹H-NMR (CDCl₃, 200 MHz): 7.87-7.80(m, 2H), 7.31-7.15 (m, 7H), 6.93-6.83 (m, 3H), 3.76 (s, 2H), 2.84 (s,4H), 2.14 (s, 3H).

EXAMPLE 4944-{2-Methyl-4-[(2-thiophen-2-yl-ethylamino)-methyl]-phenoxy}-benzamide

Compound 3 was prepared from aldehyde described in Example 492, step 2and 2-thiophen-2-yl-ethylamine using the reductive amination conditionsdescribed above Electrospray MS M+1 ion=367. ¹H-NMR (CDCl₃, 200 MHz):7.85-7.81 (m, 2H), 7.26-7.17 (m, 3H), 6.95-6.85 (m, 5H), 3.76 (s, 2H),3.10-3.02 (m, 2H), 2.91-2.84 (m, 2H), 2.15 (s, 3H).

EXAMPLE 4954-{3-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Step 1 4-(3-Chloro-4-formyl-phenoxy)-benzonitrile

Dissolve 2-chloro-4-hydroxy-benzaldehyde (1.09 g, 7.01 mmol) in DMF (10mL), add K₂CO₃ (1.06 g, 7.7 mmol) and 4-fluorobenzonitrile (932 mg, 7.7mmol), heat the mixture at 130° C. overnight. Add water and extract theaqueous layer with EtOAc. Combine organic layers and dry over Na₂SO₄.Eliminate the solvent and purify by flash chromatography on silica gel(eluent: EtOAc/hexane 15/85) to give the title compound (240 mg, 14%).¹H -NMR (CDCl₃, 300 MHz): 10.40 (s, 1H), 7.98 (d, 1H, J=8.6 Hz),7.74-7.71 (m, 2H), 7.17-7.00 (m, 4H).

Step 24-{3-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzonitrile

The reductive amination was done in the conditions described in Example492, step 3 using the aldehyde described above. The crude mixture waspurified by flash chromatography (EtOAc/hexane 20/80) to obtain thetitle compound (105 mg, 68%). Electrospray MS M+1 ion=329. ¹H-NMR(CDCl₃, 200 MHz): 7.64-7.59 (m, 2H), 7.45 (d, 1H, J=8.3 Hz), 7.09-6.92(m, 4H), 3.8 (s, 2H), 2.67 (t, 2H, J=7.5 Hz), 1.75-1.56 (m, 1H), 1.43(q, 1H, J=7.5 Hz), 0.90 (d, 6H, J=6.8 Hz).

Step 3

The compound of step 2 above is subject to hydrolysis using hydrogenperoxide and potassium carbonate. The details of the hydrolysisprocedure to form the amide form nitrile have been describedexhaustively elsewhere in this document.

¹H-NMR (CDCl₃, 200 MHz): 7.92-7.89 (m, 2H), 7.47 (d, 1H, J=8.3 Hz),7.11-6.98 (m, 4H), 3.86 (s, 2H), 2.64 (t, 2H, J=7.7 Hz), 1.66-1.55 (m,1H), 1.44 (q, 2H, J=7.7 Hz), 0.91 (d, 6H, J=6.6 Hz). ¹³C-NMR (CDCl3, 300MHz): 167.6, 157.4, 153.5, 131.9, 129.9, 129.0, 127.0, 126.3, 117.5,115.3, 115.1, 47.1, 35.5, 23.5, 19.1.

EXAMPLE 496 4-[3-Chloro-4-(phenethylamino-methyl)-phenoxy]-benzamide

Step 1 4-[3-Chloro-4-(phenethylamino-methyl)-phenoxy]-benzonitrile

The reductive amination was done in the conditions described in Example492, step 3 using the aldehyde described for compound 4 (step 1). Thecrude mixture was purified by flash chromatography (EtOAc/hexane 20/80)to obtain the title compound (101 mg, 59%). Electrospray MS M+1 ion=363.¹H-NMR (CDCl₃, 200 MHz): 7.64-7.59 (m, 2H), 7.42-7.20 (m, 6H), 7.07-6.89(m, 4H), 3.89 (s, 2H), 2.99-2.81 (m, 4H).

Step 2

The compound of step 1 above is subject to hydrolysis using hydrogenperoxide and potassium carbonate. The details of the hydrolysisprocedure to form the amide form nitrile have been describedexhaustively elsewhere in this document.

Electrospray MS M+1 ion=381. ¹H -NMR (CDCl₃, 200 MHz): 7.92-7.85 (m,2H), 7.39 (d, 1H, J=8.3 Hz), 7.30-7.12 (m, 5H), 7.06-6.91 (m, 4H), 3.84(s, 2H), 2.83 (s, 4H).

EXAMPLE 4974-{2-Ethoxy-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide(47J-3179-381, LSN 2120309)

Dissolve 3-ethoxy-4-hydroxy-benzaldehyde (2.57 g, 15.45 mmol) in DMF (20mL), add K₂CO₃ (2.33 g, 16.86 mmol) and 4-fluorobenzonitrile (1.70 g,14.05 mmol), heat the mixture at 130° C. overnight. Add water andextract the aqueous layer with EtOAc. Combine organic layers and dryover Na₂SO₄. Eliminate the solvent and purify by flash chromatography onsilica gel (eluent: EtOAc/hexane 15/85) to get a mixture of twocompounds (1.45 g). This mixture (240 mg) is submitted to the reductiveamination conditions described for compound 1 (step 3) using3-methyl-butylamine to obtain a mixture of two compounds which issubject to hydrolysis using hydrogen peroxide and potassium carbonate inthe conditions described elsewhere in this document. This mixture ispurified by flash chromatography (EtOAc and CH₂Cl₂/MeOH 10%) and thenthe title compound is isolated after HPLC (Column: XTerraMSC18 (5 um,19×100 mm). Isocratic mode: 55/45 Ammonium bicarbonate-pH9-/Acetonitrile. Flow: 10 mL/min).

¹H-NMR (CDCl₃, 200 MHz): 7.82-7.78 (m, 2H), 7.14-6.83 (m, 5H), 4.01 (q,2H, J=6.8 Hz), 3.76 (s, 2H), 2.66-2.58 (m, 2H), 1.70-1.39 (m, 3H), 1.17(t, 3H, J=7.0 Hz), 0.91 (d, 6H, J=6.7 Hz). ¹³C-NMR (CDCl3, 300 MHz):172.2, 163.6, 152.8, 144.4, 139.4, 130.8, 128.6, 123.8, 122.8, 116.9,116.3, 65.9, 54.6, 39.8, 27.9, 23.4, 15.3.

EXAMPLE 498 6-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide

Step 1 [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester

Add dropwise via an addition funnel a solution of ethyl chloroformate(0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution oftyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), andwater (7 mL). Stir at room temperature for 18 hours then pour thereaction into 1 N aqueous hydrochloric acid so the pH=1-2. Extract withethyl acetate (3×25 mL). Dry the combined ethyl acetate extracts oversodium chloride/magnesium sulfate, filter, and concentrate on a rotaryevaporator to yield 1.3 g, 6.2 mmol of[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: ¹H NMR (CDCl3,300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s 1H);4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m,3H).

Step 2 4-(2-Methylamino-ethyl)-phenol

Add dropwise via an addition funnel a solution of[2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid methyl ester (13.0 g, 62.2mmol) in tetrahydrofuran (100 mL) to a stirred solution at 0° C. of 1.0Mlithium aluminum hydride in tetrahydrofuran (156 mL) and tetrahydrofuran(250 mL). Reflux for 18 hours, cool to 0° C., quench with saturatedaqueous ammonium chloride then stir at room temperature for 3 hours.Filter off the aluminum salts, concentrate on a rotary evaporator, anddry under vacuum to yield 6.6 g of 4-(2-methylamino-ethyl)-phenol: ¹HNMR (DMSO-d6, 300.00 MHz): 6.97 (d, 2H); 6.65 (d, 2H); 2.65-2.55 (m,4H); 2.28 (s, 3H).

Step 3 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide

Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol),6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g,13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for18 hours. Cool to room temperature and evaporate on a rotary evaporatorto yield the crude product (1.3 g). The crude product is purified byflash column chromatography on silica gel eluting with 1% conc. ammoniumhydroxide/10% ethanol in chloroform then ethanol to yield6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): ¹HNMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m,2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m,4H)m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1%TFA in water) over10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.

Step 4 [2-(4-Hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butylester

Combine di-tert-butyl dicarbonate (9.7 g, 44.5 mmol),4-(2-methylamino-ethyl)-phenol (5.6 g, 37.1 mmol), and tetrahydrofuran(150 mL) and stir at room temperature for 18 hours. Concentrate on arotary evaporator to yield the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with 25%ethyl acetate in hexanes to yield[2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (7.7g, 30.7 mmol): ¹H NMR (CDCl₃, 300.00 MHz): 7.00 (d, 2H); 6.76 (d, 2H);6.39 (s, 1H); 3.40 (t, 2H); 2.81 (s, 3H); 2.73 (t, 2H); 1.42 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-methyl-carbamic acidtert-butyl ester

Combine [2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butylester (5.0 g, 19.9 mmol), 6-chloronicotinamide (3.1 g, 19.9 mmol), andcesium carbonate (12.9 g, 39.8 mmol), in N,N-dimethylformamide (90 mL),stir and heat at 85° C. for 18 hours. Cool to room temperature andevaporate on a rotary evaporator to yield the crude product (9.5 g). Thecrude product is purified by flash column chromatography on silica geleluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc.ammonium hydroxide/10% ethanol) in chloroform to yield{2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-methyl-carbamic acidtert-butyl ester (6.5 g, 17.5 mmol): ¹H NMR (CDCl₃, 300.00 MHz): 8.60(s, 1H); 8.18-8.14 (m, 1H); 7.24-7.24 (m, 2H); 7.07 (d, 2H); 6.94 (d,1H); 5.98 (br, 2H); 3.47-3.42 (m, 2H); 2.85-2.85 (m, 5H); 1.42 (s, 9H).

Step 6 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide

Add dropwise via an addition funnel, a solution of trifluoroacetic acid(30 mL) in dichloromethane (100 mL) to a stirred solution at 0° C. of{2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-methyl-carbamic acidtert-butyl ester (11.4 g, 30.7 mmol) in 1,2-dichloromethane (400 mL).Warm the mixture to room temperature and stir for 18 hours. Evaporate ona rotary evaporator to yield the crude trifluoroacetic acid salt.Dissolve the salt in methanol (150 mL) and 1,2-dichloromethane (150 mL)then combine with MP-carbonate resin (50 g @ 2.55 eq/g) (available fromArgonaut Technologies). Stir for 18 hours at room temperature, filter,wash the resin with 1,2-dichloromethane (3×75 mL), and evaporate thefiltrate on a rotary evaporator to yield6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (8.1 g, 29.9 mmol).

Step 7

Combine 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (135 mg, 0.5mmol), benzaldehyde (53 μL, 0.52 mmol), sodium triacetoxyborohydride(0.21 g, 1.0 mmol), acetic acid (30 μL, 0.52 mmol), tetrahydrofuran (1mL), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18hours. Dilute the reaction with saturated aqueous sodium bicarbonatesolution and extract with ethyl acetate (3×50 mL). Dry the combinedethyl acetate extracts with sodium chloride/magnesium sulfate, filter,and concentrate on a rotary evaporator to yield 200 mg of the crudeproduct. The crude product is purified by flash column chromatography onsilica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to(1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield6-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide (106 mg, 0.29mmol): m/z=362.07 (M+1); ¹H NMR (CDCl3, 300.00 MHz): 8.58 (s, 1H); 8.16(dd, 3.0 Hz, 1H); 7.33-7.22 (m, 7H); 7.05 (d, 2H); 6.95 (d, 1H); 5.86(br s, 2H); 3.63 (s, 2H); 2.89-2.72 (m, 4H); 2.34 (s, 3H), HPLC=100%(5/95 to 95/5 ACN/(0.1%TFA in water) over 10 minutes, Zorbax® SB-Phenyl4.6 mm×15 cm×5 micron, λ=254 nM.

By the method of Example 498 the following compounds were prepared,isolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm × 15 cm × Mass spectrum 5 micron, λ = 254 nM (ionspray): Retention Time Example Name m/z (M + 1) Purity (minutes) 4996-{4-[2-(Methyl-thiophen-2- 367.95 99 5.86 ylmethyl-amino)-ethyl]-phenoxy}-nicotinamide 500 6-(4-{2-[Methyl-(3-methyl- 342.07 99 5.91butyl)-amino]-ethyl}-phenoxy)- nicotinamide 5016-{4-[2-(Isobutyl-methyl- 327.4 97 5.73 amino)-ethyl]-phenoxy}-nicotinamide 502 6-{4-[2-(Bicyclo[2.2.1]hept-5- 378.5 99 6.03en-2-ylmethyl-methyl-amino)- ethyl]-phenoxy}-nicotinamide 5036-{4-[2-(Cyclohexylmethyl- 368.5 100 6.04 methyl-amino)-ethyl]-phenoxy}-nicotinamide 504 6-(4-{2-[Methyl-(2-phenoxy- 454.5 99 6.32benzyl)-amino]-ethyl}- phenoxy)-nicotinamide 5056-(4-{2-[Methyl-(2-methyl- 376.5 99 5.98 benzyl)-amino]-ethyl}-phenoxy)-nicotinamide 506 6-(4-{2-[(3-Chloro-benzyl)- 395.9 100 6.02methyl-amino]-ethyl}- phenoxy)-nicotinamide 5076-(4-{2-[(2-Chloro-benzyl)- 395.9 100 5.96 methyl-amino]-ethyl}-phenoxy)-nicotinamide 508 6-(4-{2-[(4-Fluoro-2- 448.4 100 6.08trifluoromethyl-benzyl)-methyl- amino]-ethyl}-phenoxy)- nicotinamide 5096-(4-{2-[(3-Bromo-4-fluoro- 458.3 100 6.04 benzyl)-methyl-amino]-ethyl}-phenoxy)-nicotinamide 510 6-(4-{2-[(2-Chloro-6-fluoro- 413.9 100 5.93benzyl)-methyl-amino]-ethyl}- phenoxy)-nicotinamide 5116-{4-[2-(Cyclohexyl-methyl- 354.5 100 5.89 amino)-ethyl]-phenoxy}-nicotinamide 512 6-(4-{2-[Methyl-(2- 446.4 99 6.13trifluoromethoxy-benzyl)- amino]-ethyl}-phenoxy)- nicotinamide 5136-(4-{2-[(3-Fluoro-benzyl)- 380.4 100 5.90 methyl-amino]-ethyl}-phenoxy)-nicotinamide 514 6-(4-{2-[Methyl-(3-phenyl-1H- 428.5 100 5.79pyrazol-4-ylmethyl)-amino]- ethyl}-phenoxy)-nicotinamide 5156-(4-{2-[(1,5a,6,9,9a,9b- 460.3 76 6.28 Hexahydro-4H-dibenzofuran-4a-ylmethyl)-methyl-amino]- ethyl}-phenoxy)-nicotinamide 5166-(4-{2-[Methyl-(2,4,6- 408.6 76 6.26 trimethyl-cyclohex-3-enylmethyl)-amino]-ethyl}- phenoxy)-nicotinamide 5176-(4-{2-[(5-Chloro-1-methyl-3- 467.9 100 5.94trifluoromethyl-1H-pyrazol-4- ylmethyl)-methyl-amino]-ethyl}-phenoxy)-nicotinamide 518 6-{4-[2-(Cyclohex-3- 366.5 86 5.94enylmethyl-methyl-amino)- ethyl]-phenoxy}-nicotinamide 5196-{4-[2-(Dec-4-enyl-methyl- 410.6 93 6.45 amino)-ethyl]-phenoxy}-nicotinamide 520 6-(4-{2-[Methyl-(2-phenyl-but- 402.5 100 6.102-enyl)-amino]-ethyl}- phenoxy)-nicotinamide 5216-(4-{2-[(3-Furan-2-yl-2- 454.5 84 6.23 phenyl-allyl)-methyl-amino]-ethyl}-phenoxy)-nicotinamide 522 6-(4-{2-[(2-Methoxy-benzyl)- 392.2 985.99 methyl-amino]-ethyl}- phenoxy)-nicotinamide 5236-(4-{2-[(3-Chloro-4-fluoro- 414.5 99 6.03 benzyl)-methyl-amino]-ethyl}-phenoxy)-nicotinamide 524 6-(4-{2-[Methyl-(3-methyl- 376.2 100 5.99benzyl)-amino]-ethyl}- phenoxy)-nicotinamide 525 6-(4-{2-[Methyl-(3-430.18 100 6.07 trifluoromethyl-benzyl)-amino]-ethyl}-phenoxy)-nicotinamide 526 6-(4-{2-[(2,6-Difluoro-benzyl)- 398.17100 5.88 methyl-amino]-ethyl}- phenoxy)-nicotinamide 5276-(4-{2-[Methyl-(3-methyl- 382.17 96 5.93 thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide 528 6-(4-{2-[Methyl-(3-phenoxy- 454.21 996.28 benzyl)-amino]-ethyl}- phenoxy)-nicotinamide 5296-(4-{2-[Methyl-(2- 430.15 100 6.03 trifluoromethyl-benzyl)-amino]-ethyl}-phenoxy)-nicotinamide 530 6-{4-[2-(Methyl-thiophen-3- 368.13 1006.85 ylmethyl-amino)-ethyl]- phenoxy}-nicotinamide 5316-{4-[2-(Cyclopentylmethyl- 354.2 100 5.93 methyl-amino)-ethyl]-phenoxy}-nicotinamide 532 6-(4-{2-[(5-Chloro-1,3- 414.18 97 5.71dimethyl-1H-pyrazol-4- ylmethyl)-methyl-amino]-ethyl}-phenoxy)-nicotinamide 533 6-(4-{2-[(2,5-Bis- 498.13 100 6.23trifluoromethyl-benzyl)-methyl- amino]-ethyl}-phenoxy)- nicotinamide 5346-(4-{2-[(3-Cyclopentyloxy-4- 476.24 100 6.18 methoxy-benzyl)-methyl-amino]-ethyl}-phenoxy)- nicotinamide 535 6-(4-{2-[(2-Fluoro-6- 448.16100 6.02 trifluoromethyl-benzyl)-methyl- amino]-ethyl}-phenoxy)-nicotinamide 536 6-(4-{2-[Methyl-(4- 422.21 100 6.04trifluoromethyl-cyclohexyl)- amino]-ethyl}-phenoxy)- nicotinamide 5376-(4-{2-[(4-Chloro-3- 464.13 100 6.17 trifluoromethyl-benzyl)-methyl-amino]-ethyl}-phenoxy)- nicotinamide 538 6-(4-{2-[Methyl-(6-methyl-380.22 90 6.05 cyclohex-3-enylmethyl)- amino]-ethyl}-phenoxy)-nicotinamide 539 6-{4-[2-(Cyclohex-1- 366.2 84 5.98enylmethyl-methyl-amino)- ethyl]-phenoxy}-nicotinamide 5404-({2-[4-(5-Carbamoyl-pyridin- 427.22 100 5.79 2-yloxy)-phenyl]-ethyl}-methyl-amino)-piperidine-1- carboxylic acid ethyl ester 5416-(4-{2-[(2-Fluoro-4- 448.16 100 6.11 trifluoromethyl-benzyl)-methyl-amino]-ethyl}-phenoxy)- nicotinamide 542 6-(4-{2-[(3,4-Dimethyl- 382.2699 6.11 cyclohexyl)-methyl-amino]- ethyl}-phenoxy)-nicotinamide 5436-(4-{2-[Methyl-(tetrahydro- 358.16 99 5.74thiophen-3-yl)-amino]-ethyl}- phenoxy)-nicotinamide 5446-{4-[2-(Bicyclo[2.2.1]hept-5- 364.5 99 5.82en-2-yl-methyl-amino)-ethyl]- phenoxy}-nicotinamide

EXAMPLE 5456-{2-Methyl-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 2-Methyl-4-(2-nitro-vinyl)-phenol

Dissolve 2-methyl-4-hydroxy-benzaldehyde (980 mg, 6.3 mmol),nitromethane (2.0 mL, 37.7 mmol) and ammonium acetate (1.9 g, 25.1 mmol)in acetic acid (9 mL). Heat eh reaction mixture at 110° C. for 2 hours.Concentrate the reaction mixture under reduced pressure and partitionthe residue between ether and water. Separate the layers and dry withNa₂SO₄, filter and concentrate under reduced pressure to afford a crudeproduct. Purify the crude by flash chromatography (eluent: EtOAc/hexane20/80 and 30/70) to afford the title compound (1.0 g). ¹H-NMR (CDCl₃,200 MHz): 7.94 (d, 1H, J=13.4 Hz), 7.50 (d, 1H, J=13.6 Hz), 7.34-7.27(m, 2H), 6.82 (d, 1H, J=8.1 Hz), 2.28 (s, 3H).

Step 2 4-(2-Amino-ethyl)-2-methyl-phenol

Procedure 1: Dissolve compound obtained in step 1 above (440 mg, 2.46mmol) in methanol (10 mL) and add Pd/C 10% (272 mg) and HCl conc (1 mL).Stir the mixture at room temperature under hydrogen overnight. Filterthe mixture over celite and evaporate the solvent to afford a crudeproduct. Purify the crude product by SCX column to obtain the titlecompound (232 mg, 63%).

Procedure 2: To lithium aluminum hydride 1.0M in ether (1.67 mL, 1.67mmol) at 0° C. a solution of aluminum trichloride (224 mg, 1.67 mmol) inTHF (2 mL) is added. After 5 min a solution of compound obtained in step1 above (100 mg, 0.56 mmol) in THF (2 mL) is added and the reaction isallowed to stir at room temperature overnight. Add water and then 3 NHCl, the aqueous layer is extracted with 3/1 n-butanol/toluene. Thecombined organic layers are dried over sodium sulfate and concentrated.SCX ion-exchange chromatography afforded 71 mg (84%) of the titlecompound. Electrospray MS M+1 ion=152. ¹H-NMR (methanol-d₄, 200 MHz):6.89 (bs, 1H), 6.82 (dd, 1H, J=8.3 and 2.4 Hz), 6.64 (d, 1H, J=8.1 Hz),2.80 (t, 2H, J=6.7 Hz), 2.61 (t, 2H, J=7.0 Hz), 2.15 (s, 3H).

Step 3 [2-(4-Hydroxy-3-methyl-phenyl)-ethyl]-carbamic acid tert-butylesther

Dissolve amine obtained in step 2 above (289 mg, 1.91 mmol) in dry THF(5 mL) under N₂ atmosphere, add a solution of di-tertbutyl dicarbonate(439 mg, 2.0 mmol) in THF (5 mL), stir the mixture at room temperatureovernight. Evaporate the solvent to obtain the title compound (462 mg,96%). TLC R_(f) (EtOAc/hexane 20/80): 0.27. ¹H-NMR (methanol-d₄, 200MHz): 6.88 (bs, 1H), 6.82 (d, 1H, J=8.3 Hz), 6.63 (d, 1H, J=8.1 Hz),3.17 (t, 2H, J=6.7 Hz), 2.60 (t, 2H, J=7.0 Hz), 2.14 (s, 3H), 1.50 (s,9H).

Step 4 {2-[4-(5-Cyano-pyridin-2-yloxy)-3-methyl-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (455 mg, 1.1 mmol),6-chloronicotinonitrile (251 mg, 1.81 mmol) and sodium hydride (87 mg,2.17 mmol) in DMSO (10 mL) is stirred at room temperature for 18 hours.Pour the mixture into ice cold water and extract the aqueous layer withEtOAc. Dry the organic layer over Na₂SO₄, filter, and concentrate thefiltrate to afford a crude product. Purify the crude product by flashcolumn chromatography (eluent: EtOAc/hexane 15/85 and 20/80) to affordthe title compound (358 mg, 57%). Electrospray MS M⁺+1-Boc group ion:298. ¹H-NMR (CDCl₃, 200 MHz): 8.42 (dd, 1H, J=0.5 and 2.4 Hz), 7.90 (dd,1H, J=2.4 and 8.6 Hz), 7.11-6.94 (m, 4H), 3.37 (q, 2H, J=7.0 Hz), 2.77(t, 2H, J=7.2 Hz), 2.10 (s, 3H), 1.43 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-3-methyl-phenyl]-ethyl}-carbamicacid tert-butyl ester

The compound of step 4 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to forman amide form the corresponding nitrile have been described previously.

¹H-NMR (CDCl₃, 200 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=2.4 and8.6 Hz), 7.09-6.90 (m, 4H), 3.38 (q, 2H, J=6.7 Hz), 2.77 (t, 2H, J=7.0Hz), 2.11 (s, 3H), 1.43 (s, 9H).

Step 6 6-[4-(2-Amino-ethyl)-2-methyl-phenoxy]-nicotinamide

To a solution of the compound of step 5 (376 mg, 1.01 mmol) in CH₂Cl₂(20 mL), add trifluoroacetic acid (2.03 mL, 26.4 mmol). Stir thereaction mixture at room temperature for 2 hours. Eliminate the solventand purify by SCX column to obtain the title compound (264 mg, 96%).Electrospray MS M⁺+1 ion: 272. ¹H-NMR (metanol-d₄, 200 MHz): 8.58 (d,1H, J=2.4 Hz), 8.24 (dd, 1H, J=2.7 and 8.9 Hz), 7.17-6.94 (m, 4H),2.94-2.86 (m, 2H), 2.78-2.71 (m, 2H), 2.10 (s, 3H).

Step 7

Combine 3-methyl-butylaldehyde (60 μl, 0.22 mmol), amine from step 6above (60 mg, 0.22 mmol) and 3 A molecular sieves (670 mg) in methanol(2 mL), stir the mixture at room temperature overnight. Add NaBH₄ (41mg, 1.10 mmol) and stir at room temperature for 3 hours. Filter themixture over celite® and concentrate the filtrate to afford a crudeproduct. Purify the crude mixture by flash chromatography (eluent:CH₂Cl₂/MeOH 80/20) to obtain the title compound (45 mg, 60%).Electrospray MS M+1 ion=342. ¹H-NMR (metanol-d₄, 200 MHz): 8.59 (dd, 1H,J=0.8 and 2.7 Hz), 8.24 (dd, 1H, J=2.4 and 8.6 Hz), 7.19-7.10 (m, 2H),7.00-6.93 (m, 2H), 2.93-2.76 (m, 4H), 2.70-2.62 (m, 2H), 2.10 (s, 3H),1.71-1.36 (m, 3H), 0.91 (d, 6H, J=6.4 Hz).

EXAMPLES 546-552

Compounds of examples 546-552 were prepared following the method ofexample 545. The purification process is described in each case

EXAMPLE 5466-{2-Methyl-4-[2-(3,3-dimethyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=356. ¹H-NMR(metanol-d₄, 200 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.24 (dd, 1H, J=2.4 and8.6 Hz), 7.18-7.10 (m, 2H), 7.00-6.94 (m, 2H), 2.92-2.78 (m, 4H),2.69-2.60 (m, 2H), 2.10 (s, 3H), 1.48-1.39 (m, 2H), 0.93 (s, 9H).

EXAMPLE 547 6-[2-Methyl-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/EtOAc/MeOH:NH₃ 2M35/60/5). Electrospray MS M+1 ion=342. ¹H-NMR (metanol-d₄, 200 MHz):8.59 (dd, 1H, J=0.5 and 2.3 Hz), 8.24 (dd, 1H, J=2.6 and 8.8 Hz),7.17-7.08 (m, 2H), 6.98-6.92 (m, 2H), 2.88-2.75 (m, 4H), 2.65-2.57 (m,2H), 2.09 (s, 3H), 1.59-1.25 (m, 6H), 0.91 (t, 3H, J=6.4 Hz).

EXAMPLE 5486-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-2-methyl-phenoxy}-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/MeOH 90/10).Electrospray MS M+1 ion=368. ¹H-NMR (metanol-d₄, 200 MHz): 8.59 (d, 1H,J=2.4 Hz), 8.24 (dd, 1H, J=2.7 and 8.6 Hz), 7.18-7.10 (m, 2H), 7.00-6.93(m, 2H), 2.85 (bs, 4H), 2.50 (d, 2H, j=6.4 Hz), 2.10 (s, 3H), 1.77-0.84(m, 11H).

EXAMPLE 5496-{4-[2-(3-Fluoro-benzylamino)-ethyl]-2-methyl-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=380. ¹H-NMR(metanol-d₄, 200 MHz): 8.59 (dd, 1H, J=0.5 and 2.4 Hz), 8.24 (dd, 1H,J=2.4 and 8.6 Hz), 7.38-6.92 (m, 8H), 3.79 (s, 2H), 2.82 (s, 4H), 2.09(s, 3H).

EXAMPLE 5506-{4-[2-(3-Fluoro-benzylamino)-ethyl]-2-methyl-phenoxy}-nicotinamide,mesylate salt

Example 5 (free amine of example 6) was dissolved in THF, thenmethanosulfonic acid was added (1.0 eq), the mixture was stirred for 1hour and the solvent eliminated to give the title compound. ElectrosprayMS M+1 ion=380. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (bs, 1H), 8.28 (dd,1H, J=1.4 and 8.7 Hz), 7.56-7.02 (m, 8H), 4.30 (s, 2H), 3.36 (t, 2H,J=7.3 Hz), 3.06 (t, 2H, J=7.3 Hz), 2.72 (s, 3H), 2.14 (s, 3H).

EXAMPLE 5516-(4-{2-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-ethyl}-2-methyl-phenoxy)-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH9/B=CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=378. ¹H-NMR (metanol-d₄, 200 MHz): 8.59 (d, 1H, J=2.6 Hz), 8.24(dd, 1H, J=2.4 and 8.6 Hz), 7.16-6.91 (m, 4H), 6.16-5.88 (m, 2H),2.81-1.81 (m, 9H), 2.09 (s, 3H), 1.65-0.99 (m, 3H), 0.57-0.48 (m, 1H).

EXAMPLE 5526-[4-(2-Cyclooctylamino-ethyl)-2-methyl-phenoxy]-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/MeOH 70/30).Electrospray MS M+1 ion=382 ¹H-NMR (metanol-d₄, 200 MHz): 8.50 (d, 1H,J=2.4 Hz), 8.24 (dd, 1H, J=2.4 and 8.6 Hz), 7.18-6.92 (m, 4H), 2.95-2.77(m, 5H), 2.12 (m, 1H), 2.10 (s, 3H), 1.89-1.46 (m, 13H).

EXAMPLE 5536-{3-Chloro-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 3-Chloro-4-(2-nitro-vinyl)-phenol

The 3-chloro-4-hydroxy-benzaldehyde (980 mg, 6.3 mmol), nitromethane(2.0 mL, 37.7 mmol) and ammonium acetate (1.9 g, 25.1 mmol) weredissolved in acetic acid (9 mL) and the reaction heated at 110° C. for 2hours. The reaction is concentrated under reduced pressure and theresidue partitioned between ether and water. Separate the layers and drywith Na₂SO₄, filter and concentrate under reduced pressure. Purify thecrude product by flash chromatography (eluent: EtOAc/hexane 20/80 and30/70) afforded the title compound (1.0 g, 80%). ¹H-NMR (CDCl₃, 200MHz): 8.34 (d, 1H, J=13.4 Hz), 7.82 (d, 1H, J=13.4 Hz), 7.71 (d, 1H,J=8.6 Hz), 6.94 (d, 1H, J=2.4 Hz), 6.80 (dd, 1H, J=2.4 and 8.6 Hz).

Step 2 4-(2-Amino-ethyl)-3-choloro-phenol

To lithium aluminum hydride 1.0M in ether (1.50 mL, 1.50 mmol) at 0° C.a solution of aluminum trichloride (201 mg, 1.51 mmol) in THF (2 mL) isadded. After 5 min a solution of compound obtained in step 1 above (100mg, 0.50 mmol) in THF (2 mL) is added and the reaction is allowed tostir at room temperature overnight. Add water and then 3 N HCl. Extractthe aqueous layer with 3/1 n-butanol/toluene. The combined organiclayers are dried over sodium sulfate and concentrated. SCX ion-exchangechromatography of the concentrate afforded 70 mg (81%) of the titlecompound. Electrospray MS M+1 ion=172. ¹H-NMR (methanol-d₄, 200 MHz):7.06 (d, 1H, J=8.3 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.65 (dd, 1H, J=2.4 and8.3 Hz), 2.82 (m, 4H).

Step 3 [2-(4-Hydroxy-2-chloro-phenyl)-ethyl]-carbamic acid tert-butylester

Dissolve amine obtained in step 2 above (620 mg, 3.62 mmol) in dry THF(20 mL) and DMF (1 mL) under N₂ atmosphere, add a solution ofdi-tertbutyl dicarbonate (791 mg, 3.62 mmol) in THF (10 mL), stir themixture at room temperature overnight. Concentrate the mixture to acrude product and purify the crude product by flash chromatography(eluent: EtOAc/hexane 30/70) to obtain the title compound (670 mg, 68%).TLC R_(f) (EtOAc/hexane 20/80): 0.27. ¹H-NMR (methanol-d₄, 200 MHz):7.06 (d, 1H, J=8.3 Hz), 6.78 (d, 1H, J=2.6 Hz), 6.65 (dd, 1H, J=2.4 and8.3 Hz), 3.21 (t, 2H, J=6.7 Hz), 2.78 (t, 2H, J=7.5 Hz), 1.41 (s, 9H).

Step 4 {2-[4-(5-Cyano-pyridin-2-yloxy)-2-chloro-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (650 mg, 2.4 mmol),6-chloronicotinonitrile (333 mg, 2.4 mmol) and sodium hydride (115 mg,2.9 mmol) in DMSO (12 mL) is stirred at room, temperature for 18 hours.Pour the mixture into cold water (about 0° C.) and extract the aqueouslayer with EtOAc. Dry the organic layer over Na₂SO₄, filter andconcentrate the filtrate to afford a crude product. Purify the crudeproduct by flash chromatography (eluent: EtOAc/hexane 20/80 and 30/70)to afford the title compound (810 mg, 90%). Electrospray MS M⁺+1-Bocgroup ion: 318. ¹H-NMR (CDCl₃, 200 MHz): 8.46 (dd, 1H, J=0.5 and 2.2Hz), 7.94 (dd, 1H, J=2.4 and 8.6 Hz), 7.31-7.18 (m, 2H), 7.06-6.98 (m,2H), 3.41 (q, 2H, J=6.7 Hz), 2.95 (t, 2H, J=7.3 Hz), 1.44 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-2-chloro-phenyl]-ethyl}-carbamicacid tert-butyl esther

The compound of step 4 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to formanalogous amides from the corresponding nitrile have been describedpreviously.

¹H-NMR (methanol-d₄, 200 MHz): 8.62 (dd, 1H, J=0.8 and 2.7 Hz), 8.27(dd, 1H, J=2.4 and 8.6 Hz), 7.34 (d, 1H, J=8.3 Hz), 7.22 (d, 1H, J=2.4Hz), 7.07-7.02 (m, 2H), 3.34 (m, 2H), 2.92 (t, 2H, J=7.3 Hz), 1.42 (s,9H).

Step 6 6-[4-(2-Amino-ethyl)-2-chloro-phenoxy]-nicotinamide

The compound of step 5 is subjected to hydrolysis using trifluoroaceticacid. The details of the hydrolysis procedure to remove the protectinggroup have been described previously. Electrospray MS M+1 ion=292.¹H-NMR(metanol-d₄, 200 MHz): 8.60 (dd, 1H, J=0.8 and 2.7 Hz), 8.28 (dd, 1H,J=2.7 and 8.9 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=2.4 Hz),7.09-7.03 (m, 2H), 2.94 (s, 4H).

Step 7

Combine compound from step 6 (60 mg, 0.21 mmol), 3-methyl-butyraldehyde(24 μl, 0.23 mmol) and 3 A molecular sieves (670 mg) in methanol (2 mL),stir the mixture at room temperature overnight. Add NaBH₄ (41 mg, 1.10mmol) and stir at room temperature for 3 hours. Filter the mixture overcelite. Concentrate the filtrate to afford the crude product. Purify thecrude product using an SCX column to obtain the title compound.Electrospray MS M+1 ion=362. ¹H-NMR (metanol-d₄, 200 MHz): 8.61 (dd, 1H,J=0.8 and 2.7 Hz), 8.27 (dd, 1H, J=2.4 and 8.6 Hz), 7.38 (d, 1H, J=8.6Hz), 7.22 (d, 1H, J=2.4 Hz), 7.07-7.03 (m, 2H), 3.03-2.81 (m, 4H),2.70-2.62 (m, 2H), 1.62 (m, 1H), 1.48-1.37 (m, 2H), 0.92 (d, 6H, J=6.5Hz).

EXAMPLES 554-558

Compounds of examples 554-558 were prepared following procedures similarto that of Example 553. The purification process is described in eachcase.

EXAMPLE 5546-{3-Chloro-4-[2-(3,3-dimethyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=376. ¹H-NMR(metanol-d₄, 200 MHz): 8.61 (dd, 1H, J=0.5 and 2.4 Hz), 8.27 (dd, 1H,J=2.7 and 8.9 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.22 (d, 1H, J=2.4 Hz),7.09-7.03 (m, 2H), 3.02-2.81 (m, 4H), 2.69-2.61 (m, 2H), 1.49-1.40 (m,2H), 0.93 (s, 9H).

EXAMPLE 555 6-[3-Chloro-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: flash chromatography (eluent: CH₂Cl₂/MeOH 90/10).Electrospray MS M+1 ion=362. ¹H-NMR (metanol-d₄, 200 MHz): 8.61 (dd, 1H,J=0.8 and 2.4 Hz), 8.27 (dd, 1H, J=2.4 and 8.6 Hz), 7.38 (d, 1H, J=8.3Hz), 7.23 (d, 1H, J=2.4 Hz), 7.09-7.03 (m, 2H), 3.03-2.81 (m, 4H),2.68-2.61 (m, 2H), 1.61-1.47 (m, 2H), 1.37-1.28 (m, 4H), 0.93 (t, 3H,J=6.7 Hz).

EXAMPLE 5566-{3-Chloro-4-[2-(cyclohexylmethyl-amino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=388. ¹H-NMR(metanol-d₄, 300 MHz): 8.63 (d, 1H, J=1.8 Hz), 8.28 (dd, 1H, J=2.4 and8.5 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.22 (d, 1H, J=2.2 Hz), 7.07-7.03 (m,2H), 3.01-2.81 (m, 4H), 2.49 (d, 2H, J=6.7 Hz), 1.79-1.68 (m, 5H),1.61-1.42 (m, 1H), 1.38-1.17 (m, 3H), 0.99-0.85 (m, 2H).

EXAMPLE 5576-{3-Chloro-4-[2-(3-fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion 400. ¹H-NMR(metanol-d₄, 300 MHz): 8.63 (d, 1H, J=2.2 Hz), 8.27 (dd, 1H, J=2.4 and8.7 Hz), 7.36-6.95 (m, 8H), 3.82 (s, 2H), 3.01-2.81 (m, 4H).

EXAMPLE 5586-(4-{2-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-ethyl}-3-chloro-phenoxy)-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=398. ¹H-NMR(metanol-d₄, 200 MHz): 8.61 (dd, 1H, J=0.5 and 2.4 Hz), 8.26 (dd, 1H,J=2.4 and 8.6 Hz), 7.40-7.03 (m, 4H), 6.18-5.92 (m, 2H), 3.01-2.66 (m,6H), 2.40-2.18 (m, 2H), 1.95-1.83 (m, 1H), 1.64-1.11 (m, 3H), 0.60-0.50(m, 1H).

EXAMPLE 5596-{2,6-Difluoro-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 2,6-Difluoro-4-(2-nitro-vinyl)-phenol

3,5-Difluoro-4-hydroxybenzaldehyde (2.27 g, 14.4 mmol), nitromethane(4.7 mL, 86.4 mmol) and ammonium acetate (4.4 g, 57.6 mmol) weredissolved in acetic acid (22 mL) and the reaction mixture was heated at110° C. for 1 hour 30 min. The reaction was concentrated under reducedpressure and the residue partitioned between ether and water. The layerswere separated and the organic layer was dried with Na₂SO₄. The organicmixture was filtered and the filtrate concentrated under reducedpressure to afford a crude product. The crude product was purified byflash column chromatography (eluent: EtOAc/hexane 22/78) to afford thetitle compound (2.05 g, yield: 71%). Electrospray MS M−1 ion=200. ¹H-NMR(CDCl₃, 200 MHz): 7.84 (d, 1H, J=13.7 Hz), 7.45 (d, 1H, J=13.7 Hz),7.19-6.99 (m, 2H).

Step 2 4-(2-Amino-ethyl)-2,6-difluoro-phenol

To lithium aluminum hydride 1.0M in ether (30 mL, 29.8 mmol) at 0° C. asolution of aluminum trichloride (4.0 g, 29.8 mmol) in THF (40 mL) isadded. After 5 min a solution of compound obtained in step 1 above (2.0g, 9.95 mmol) in THF (40 mL) is added and the reaction is allowed tostir at room temperature overnight. Add water and then 3 N HCl, theaqueous layer is extracted with 3/1 n-butanol/toluene. The combinedorganic layers are dried over sodium sulfate and concentrated. SCXion-exchange chromatography afforded 1.50 g (87%) of the title compound.Electrospray MS M+1 ion=174. ¹H-NMR (methanol-d₄, 200 MHz): 6.95-6.78(m, 2H), 3.14 (t, 2H, J=7.0 Hz), 2.86 (t, 2H, J=7.3 Hz).

Step 3 [2-(3,5-Difluoro-4-hydroxy-phenyl)-ethyl]-carbamic acidtert-butyl ester

Dissolve amine obtained in step 2 above (1.5 g, 8.67 mmol) in dry THF(22 mL) under N₂ atmosphere, add a solution of di-tertbutyl dicarbonate(1.89 g, 8.67 mmol) in THF (22 mL), stir the mixture at room temperatureovernight. Eliminate the solven. Purify by flash chromatography (eluent:EtOAc/hexane 1/4 and 1/1) to obtain the desired compound (1.40 g).¹H-NMR (CDCl₃, 200 MHz): 6.85-6.66 (m, 2H), 3.31 (q, 2H, J=6.2 Hz), 2.69(t, 2H, J=7.0 Hz), 1.44 (s, 9H).

Step 4{2-[4-(5-Cyano-pyridin-2-yloxy)-3,5-difluoro-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (1.31 g; 4.8 mmol),6-chloronicotinonitrile (700 mg, 5.04 mmol) and sodium hydride (290 mg,7.2 mmol) in DMSO (25 mL) is stirred at room temperature for 18 hours.Pour the mixture into iced water and extract the aqueous layer withEtOAc. Dry the organic layer over Na₂SO₄, filtrate and eliminate thesolvent. Purify by flash chromatography (EtOAc/hexane 20/80 and 34/66)to get the title compound (950 mg, 51%). ¹H-NMR (CDCl₃, 200 MHz): 8.41(dd, 1H, J=0.8 and 2.1 Hz), 7.97 (dd, 1H, J=2.4 and 8.6 Hz), 7.18 (dd,1H, J=0.8 and 8.6 Hz), 6.92-6.81 (m, 2H), 3.39 (q, 2H, J=6.9 Hz), 2.81(t, 2H, J=6.7 Hz), 1.45 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-3,5-difluro-phenyl]-ethyl}-carbamicacid tert-butyl esther

The compound of step 4 is subjected to hydrolysis using hydrogenperoxide and potassium carbonate. The details of the hydrolysisprocedure to form analogous amides from the corresponding nitrile havebeen described previously.

¹H-NMR (metanol-d₄, 300 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H.J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-6.98 (m, 2H), 3.35-3.30(m, 2H), 2.81 (t, 2H, J=7.1 Hz), 1.44 (s, 9H).

Step 6 6-[4-(2-Amino-ethyl)-2,6-difluoro-phenoxy]-nicotinamide

To a solution of compound of step 5 (930 mg, 2.37 mmol) in CH₂Cl₂ (50mL), trifluoroacetic acid is added (4.7 mL, 61.5 mmol). Stir thereaction mixture at room temperature for 2 h. Eliminate the solvent andpurify by SCX column to obtain the title compound (658 mg, 95%).Electrospray MS M⁺+1 ion: 294. ¹H-NMR (metanol-d₄, 200 MHz): 8.56 (d,1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4 and 8.9 Hz), 7.18 (d, 1H, J=8.9 Hz),7.05-6.95 (m, 2H), 2.96-2.74 (m, 4H).

Step 7

Combine 3-methyl-butylaldehyde (26 μl, 0.24 mmol), amine from step 6above and 3 A molecular sieves (900 mg) in methanol (3 mL), stir themixture at room temperature overnight. Add NaBH₄ (45 mg, 1.20 mmol) andstir at room temperature for 3 hours. Filtrate the mixture over celiteand eliminate the solvent. Submit the crude to a SCX column to obtain asolid witch was further purified by HPLC (Column: X-Terra MS C18. A=10Mm NH₄HCO₃ pH8/B=CH₃CN. Gradient mode: from 30 to 70% B. Flow rate: 1mL/min) to obtain the title compound (42 mg). Electrospray MS M+1ion=364. ¹H-NMR (metanol-d₄, 300 MHz): 8.60 (d, 1H, J=2.0 Hz), 8.32 (dd,1H, J=2.2 and 8.5 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.01-6.98 (m, 2H), 2.85(m, 4H), 2.63 (m, 2H), 1.62 (m, 1H), 1.42 (q, 1H, J=7.3 Hz), 0.92 (d,6H, J=6.5 Hz).

By the method of example 559 the following examples (examples 560-563)were prepared. The purification process is described in each case

EXAMPLE 5606-{4-[2-(3,3-Dimethyl-butylamino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B=CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min ). Electrospray MSM+1 ion=378. ¹H-NMR (metanol-d₄, 300 MHz): 8.48 (d, 1H, J=2.4 Hz), 8.23(dd, 1H, J=2.4 and 8.5 Hz), 7.12 (d, 1H, J=8.5 Hz), 7.00-6.93 (m, 2H),2.91-2.78 (m, 4H), 2.67-2.61 (m, 2H), 1.43-1.38 (m, 2H), 0.87 (s, 9H).

EXAMPLE 5616-[2,6-Difluoro-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B=CH₃CN.Gradient mode: from 25 to 70% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=364. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.32(dd, 1H, J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-7.00 (m, 2H),2.88 (m, 4H), 2.65 (t, 2H, J=2.4 and 1.55 (m, 2H), 1.35 (m, 4H), 0.93(t, 3H, J=6.7 Hz).

EXAMPLE 5626-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B=CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=390. ¹H-NMR (metanol-d₄, 300 MHz): 8.48 (d, 1H, J=2.4 Hz), 8.23(dd, 1H, J=2.4 and 8.9 Hz), 7.11 (d, 1H, J=8.8 Hz), 6.99-6.92 (m, 2H),2.83 (m, 4H), 2.47 (d, 2H, J=6.9 Hz), 1.72-1.59 (m, 5H), 1.55-1.41 (m,1H), 1.31-1.05 (m, 3H), 0.94-0.81 (m, 2H).

EXAMPLE 5636-{4-[2-(Cyclopropylmethyl-amino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B=MeOH.Gradient mode: from 35 to 80% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=348. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.32(dd, 1H, J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-7.00 (m, 2H),2.93-2.83 (m, 4H), 2.50 (d, 2H, J=6.9 Hz), 1.10-0.90 (m, 1H), 0.55-0.49(m, 2H), 0.20-0.15 (m, 2H).

EXAMPLE 5646-(2-Pentyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 1-bromopentane (0.176 g, 1.16 mmol) in DMF (5.3 mL). Beat at 70° C.overnight and then increase the temperature to 100° C. for additionaltwo hours. Cool the reaction mixture to room temperature and add ethylacetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), drythe organic layer over Na₂SO₄, filter and concentrate. Purify by flashchromatography eluting with 7% to 15% (2.0 M NH₃ in methanol) in ethylacetate to give the title compound : MS ES⁺354.2 (M+H)⁺, HRMS calcd forC₂₁H₂₈N₃O₂ 354.2182 (M+H)⁺, found 354.2188, time 0.53 min; Anal. Calcdfor C₂₁H₂₇N₃O₂: C, 71.36; H, 7.70 N, 11.89. Found: C, 71.14; H, 7.60; N,11.79.

EXAMPLE 5656-(2-Hexyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 1-bromohexane (0.192 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C.overnight, then increase the temperature to 100° C. for additional twohours. Cool the reaction mixture to room temperature and add ethylacetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), drythe organic layer over Na₂SO₄, filter and concentrate. Purify by flashchromatography eluting with 7% to 15% (2.0 M NH₃ in methanol) in ethylacetate to give the title compound: MS ES⁺368.2 (M+H)⁺, HRMS calcd forC₂₂H₃₀N₃O₂ 368.2338 (M+H)⁺, found 368.2334, time 0.53 min; HPLC [YMC-Propack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05%TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min],t_(R)=11.6 min, 97.8% purity.

EXAMPLE 5666-[2-(2-Morpholin-4-ylethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 4-(2-chloroethyl)morpholine hydrochloride (0.217 g, 1.16 mmol) inDMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture toroom temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH(1×50 mL), brine (1×50 mL), dry the organic layer over Na₂SO₄, filterand concentrate. Purify by flash chromatography eluting with 10% to 20%(2.0 M NH₃ in methanol) in acetone to give the title compound: MSES⁺397.2 (M+H)⁺, HRMS calcd for C₂₂H₂₉N₄O₃ 397.2240 (M+H)⁺, found397.2223, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18 min], t_(R)=5.6 min, 99.0% purity.

EXAMPLE 5676-[2-(3-Morpholin-4-ylpropyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 4-(3-chloropropyl)morpholine (0.191 g, 1.16 mmol) in DMF (5.3 mL).Heat at 90° C. overnight. Cool the reaction mixture to room temperatureand add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine(1×50 mL), dry the organic layer over Na₂SO₄, filter and concentrate.Purify by flash chromatography eluting with 10% (2.0 M NH₃ in methanol)in acetone to give the title compound: MS ES⁺411.2 (M+H)⁺, HRMS calcdfor C₂₃H₃₁N₄O₃ 411.2396 (M+H)⁺, found 411.2389, time 0.48 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min],t_(R)=5.7 min, 100% purity.

EXAMPLE 5686-(2-Heptyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 1-bromoheptane (0.199 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C.overnight, then increase the temperature to 80° C. for 3.5 hours. Coolthe reaction mixture to room temperature and add ethyl acetate (100 mL).Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer overNa₂SO₄, filter and concentrate. Purify by flash chromatography elutingwith 6% to 15% (2.0 M NH₃ in methanol) in ethyl acetate to give thetitle compound: MS ES⁺382.2 (M+H)⁺, HRMS calcd for C₂₃H₃₂N₃O₂ 382.2495(M+H)⁺, found 382.2489, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0mL/min, 10-20% over 5 min, 20-95% over 18 min], t_(R)=12.6 min, 98.6%purity.

EXAMPLE 5696-[2-(3-Cyclohexylpropyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL).Heat at 50° C. overnight, then increase the temperature to 80° C. for3.5 hours. Cool the reaction mixture to room temperature and add ethylacetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry theorganic layer over Na₂SO₄, filter and concentrate. Purify by flashchromatography eluting with 6% to 15% (2.0 M NH₃ in methanol) in ethylacetate to give the title compound: MS ES⁺408.3 (M+H)⁺, HRMS calcd forC₂₅H₃₄N₃O₂ 408.2651 (M+H)⁺, found 408.2652, time 0.46 min; HPLC [YMC-Propack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05%TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min],t_(R)=13.3 min, 100% purity.

EXAMPLE 5706-[2-(3,3-Dimethylbutyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL).Heat at 70° C. overnight. Cool the reaction mixture to room temperatureand add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine(1×30 mL). Dry the organic layer over Na₂SO₄, filter and concentrate.Purify by flash chromatography eluting with 6% to 15% (2.0 M NH₃ inmethanol) in ethyl acetate to give the title compound : MS ES⁺368.2(M+H)⁺, HRMS calcd for C₂₂H₃₀N₃O₂ 368.2338 (M+H)⁺, found 368.2321, time0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18 min], t_(R)=11.1 min, 96.8% purity.

EXAMPLE 5716-[2-(2-Ethylbutyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 3-bromomethylpentane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at70° C. overnight. Cool the reaction mixture to room temperature and addethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL).Dry the organic layer over Na₂SO₄, filter and concentrate. Purify byflash chromatography eluting with 6% to 15% (2.0 M NH₃ in methanol) inethyl acetate to give the title compound: MS ES⁺368.2 (M+H)⁺, HRMS calcdfor C₂₂H₃₀N₃O₂ 368.2338 (M+H)⁺, found 368.2324, time 0.55 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min],t_(R)=10.9 min, 100% purity.

EXAMPLE 5726-[2-(2-tert-Butoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Part A: 2-tert-Butoxyethyl methanesulfonate

At 0° C. add triethylamine (35.4 mL, 254 mmol) to a stirring solution of2-tert-butoxyethanol (10.0 g, 84.6 mmol) and methanesulfonic chloride(13.1 mL, 169 mmol) in dichloromethane (169 mL). Allow the reactionmixture to warm to room temperature over night. Dilute the reactionmixture with dichloromethane (200 mL) and wash it with water (1×100 mL),1.0 N HCl (1×100 mL) and 1.0 N NaOH (1×100 mL). Dry the organic layerover MgSO₄, filter and concentrate to give the title compound: ¹H NMR(CHCl₃-d₆) 4.33 (t, 2H), 3.62 (t, 2H), 3.06 (s, 3H), 1.21 (s, 9H);GC/MS, t_(R) 13.7 min % of total 92.9%.

Part B:6-[2-(2-tert-Butoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.300 g, 1.06 mmol), K₂CO₃ (0.366 g, 2.65 mmol),and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3mL). Heat at 70° C. overnight. Cool the reaction mixture to roomtemperature and add ethyl acetate (100 mL). Wash with water (1×30 mL)and brine (1×30 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify by flash chromatography eluting with 6% to 15% (2.0M NH₃ in methanol) in ethyl acetate to give the title compound: MSES⁺384.2 (M+H)⁺, HRMS calcd for C₂₂H₃₀N₃O₃ 384.2287 (M+H)⁺, found384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18 min], t_(R)=10.5 min, 97.7% purity.

EXAMPLE 5736-[2-(4,4,4-Trifluorobutyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.350 g, 1.24 mmol), K₂CO₃ (0.427 g, 3.09 mmol),and 4-bromo-1,1,1-trifluorobutane (0.248 g, 1.30 mmol) in DMF (6.2 mL).Beat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool thereaction mixture to room temperature and add ethyl acetate (100 mL).Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layerover Na₂SO₄, filter and concentrate. Purify by flash chromatographyeluting with 6% to 20% (2.0 M NH₃ in methanol) in ethyl acetate to givethe title compound: MS ES⁺394.2 (M+H)⁺, HRMS calcd for C₂₀H₂₃N₃O₂F₃394.1742 (M+H)⁺, found 394.1733, time 0.53 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], t_(R)=10.1 min, 100%purity.

EXAMPLE 5746-(2-Butyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide(Example 447, Part E, 0.350 g, 1.24 mmol), K₂CO₃ (0.427 g, 3.09 mmol),and 1-bromobutane (0.178 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C.for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture toroom temperature and add ethyl acetate (100 mL). Wash with water (1×30mL) and brine (1×30 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify by flash chromatography eluting with 6% to 20% (2.0M NH₃ in methanol) in ethyl acetate to give the title compound: MSES⁺340.2 (M+H)⁺, HRMS calcd for C₂₀H₂₆N₃O₂ 340.2025 (M+H)⁺, found340.2019, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18 min], t_(R)=9.6 min, 98.3% purity.

INTERMEDIATES FOR EXAMPLES 575-578 Intermediate 1A6-Methoxy-1,2,3,4-tetrahydro-isoquinoline

Combine 2-(3-methoxyphenol)ethylamine (10.0 g, 66.13 mmol), 88% Formicacid, and paraformaldehyde (2.05 g, 68.25 mmol) at 0° C. Stir at roomtemperature for 24 hours and concentrate under reduced pressure. Addacetyl chloride (5 mL) in MeOH (80 mL) at room temperature and stir for10 minutes. After concentration, triturate the reaction mixture withethyl acetate, cool to room temperature, and filter to afford 8.76 g,53.7 mmol (81% yield) of the title compound as a white solid: ¹H NMR(500 MHz, CD₃OD); 3.05-13.15 (2H, m), 3.45-3.55 (2H, m), 3.70 (3H, s),4.30 (2H, s), 4.8-5.0 (1H, br s), 6.8-6.9 (2H, m), 7.1-7.2 (1H, m); MSm/z 163 (M+).

Intermediate 2A 6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline NF7-AOO344-183

Combine 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (5.0 g, 20.5 mmol) and48% aq HBr (20 mL) at room temperature. Heat the reaction at reflux for24 hours, cool the reaction to room temperature, and concentrate underreduced pressure. Triturate with ethyl acetate and filter to afford 5.5g, 20.5 mmol (99% yield) of the title compound as a tan solid: ¹H NMR(500 MHz, DMSO-d₆); 2.8-2.9 (2H, m), 3.3-3.4 (2H, m), 4.1 (2H, s),6.5-6.7 (2H, m), 6.9-7.1 (1H, m), 8.8-9.0 (2H, br s), 9.4-9.5 (1H, s).

Intermediate 3A 6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine 6-hydroxy-1,2,3,4-tetrahydroisoquinoline (5.5 g, 23.9 mmol), THF(100 mL), Et₃N (8.3 mL, 59.8 mmol), and BOC-anhydride (8.3 g, 28.7mmol). Stir at room temperature for 72 hours under nitrogen, concentrateunder reduced pressure and then flash chromatograph using 1:1hexanes:ethyl acetate eluent to afford 3.51 g, 14.1 mmol (59% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 1.5 (9H, br s), 2.7-2.8(2H, m), 3.5-3.6 (2H, m), 4.4 (2H, s), 6.5-6.8 (2H, m), 6.9-7.0 (1H, m);MS m/z 150 (M+1-CO₂t-Bu).

Intermediate 4A6-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine in a round bottom flask equipped with a Dean Stark trap6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 mL and 30 mLrespectively), K₂CO₃ (1.25 g, 9.04 mmol), and 4-fluorobenzonitrile (0.72g, 6.04 mmol). Reflux the reaction under a nitrogen atmosphere for 4hours then cool to room temperature. Add water to the reaction mixtureand extract the product from the water layer using ethyl acetate. Theproduct, a white solid, precipitates out from the ethyl acetate toafford 1.93 g, 5.5 mmol (87% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H,s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.5-7.6 (2H, m);MS m/z 249 (M−CO₂t-Bu).

Intermediate 5A6-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester NF7-AOO344-181

Combine 6-(4-cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.93 g, 5.51 mmol), t-butyl alcohol (50 mL), andKOH (1.56 g, 27.6 mmol). Stir for 72 hours at room temperature,concentrate under reduced pressure then add ethyl acetate. Wash theethyl acetate solution with a brine solution and dry the organic layerover Na₂SO₄. After concentrating the organic layer under reducedpressure, the reaction affords 1.93 g, 2.50 mmol (95% yield) of thetitle compound as a white solid: ¹H NMR (500 MHz, CDCl₃); 1.5 (9H, s),2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m),6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.7-7.9 (2H, m); TLC R_(f)=0.5 by 2:1hexanes:ethyl acetate eluent.

Intermediate 6A 4-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-benzamide

Combine 6-(4-carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 10.83 mmol), CH₂Cl₂ (100 mL), and TFA (25mL) at room temperature. Stir for 24 hours, followed by the addition of1.0 M K₂CO₃ (aq), and extract the product out of the aqueous layer withseveral washings of ethyl acetate/THF. Concentrate the organic phaseunder reduced pressure and add to 2, 10 g SCX Columns pre-treated with5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, elutewith 1.0 N NH₃-MeOH solution to afford 2.08 g, 7.7 mmol (71% yield) ofthe title compound as a white foam: ¹H NMR (500 MHz, DMSO-d₆); 2.9-3.1(2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2(3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H,m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).

EXAMPLE 5754-(2-Pentyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Combine 4-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide (80.0 mg,0.30 mmol), DMF (4 mL), Et₃N (0.2 mL, 1.32 mmol), and pentylbromide (0.1mL, 0.66 mmol) in a 7 mL vial. Place the vial on a shaker at 70° C. for72 hours and then add ethyl acetate to the reaction vial. Wash withwater and several times with 10% LiCl (aq), and dry over Na₂SO₄.Concentrate the organic mixture and flash chromatograph using 2% 1.0 NNH₃ in MeOH, 20% THF, 78% CH₂Cl₂ to afford 78.0 mg (77% yield) of thetitle compound: ¹H NMR (500 MHz, CDCl₃); 0.9-1.0 (3H, m), 1.3-1.4 (4H,m), 1.5-1.7 (2H, m), 2.4-2.6 (2H, m), 2.7-2.8 (2H, m), 2.8-3.0 (2H, m),3.5-3.6 (2H, m), 6.8-6.8 (2H, m), 6.9-7.1 (3H, m), 7.7-7.9 (2H, m); MSm/z 339 (M+1).

EXAMPLE 5764-[2-(3-Methyl-butyl)-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-benzamide

Using a method similar to Example 575, using isoamylbromide (0.1 mL,0.66 mmol) gives 63.0 mg (62% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 0.9-1.0 (6H, m), 1.4-1.8 (3H, m), 2.5-2.6 (2H, m), 2.7-2.8(2H, m), 2.9-3.0 (2H, m), 3.6-3.8 (2H, m), 6.8-7.1 (5H, m), 7.7-7.9 (2H,m); MS m/z 339 (M+1).

EXAMPLE 5774-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Using a method similar to Example 575, using benzylbromide (0.1 mL, 0.66mmol) gives 81.0 mg (75% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 2.6-2.8 (2H, m), 2.8-3.0 (2H, m), 3.5-3.7 (4H, m), 5.6-6.1 (2H,br s), 6.7-6.8 (2H, m), 6.8-7.0 (3H, m), 7.2-7.4 (5H, m), 7.7-7.9 (2H,m); MS m/z 359 (M+1).

EXAMPLE 5784-(5-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Using a method similar to Example 575, using intermediate 1A, andphenethylbromide (0.1 mL, 0.66 mmol) gives 81.9 mg (73% yield) of thetitle compound: ¹H NMR (500 MHz, CDCl₃); 2.7-3.0 (7H, m), 3.6-3.8 (3H,m), 5.8-6.2 (2H, br, s), 6.8-7.1 (5H, m), 7.2-7.4 (5H, m), 7.7-7.9 (2H,m); MS m/z 373 (M+1).

Intermediate 7A6-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine in a round bottom flask equipped with a Dean Stark trap6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(5.42 g, 21.74 mmol), toluene, dimethylacetamide (30 mL and 90 mLrespectively), K₂CO₃ (4.51 g, 32.61 mmol), and 6-chloronicatinamide(3.40 g, 21.74 mmol). Reflux the reaction under a nitrogen atmospherefor 4 hours then cool to room temperature. Add water to the reactionmixture and extract the product from the water layer using ethylacetate. The product, a white solid, precipitates out from the ethylacetate to afford 5.8 g, 15.7 mmol (72% yield) of the title compound: ¹HNMR (500 MHz, DMSO-d₆); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.5-3.6 (2H, m),4.4-4.6 (2H, m), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.5(1H, s), 8.1 (1H, s), 8.2-8.3 (1H, m), 8.6 (1H, m).

Intermediate 8A 6-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-nicotinamide

Combine6-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 10.83 mmol), CH₂Cl₂ (100 mL), and TFA (25mL). Stir at room temperature for 12 hours and add 1.0 M K₂CO₃ and CHCl₃to the reaction. Separate the organic layer, wash with brine, and dryover Na₂SO₄. Concentrate under reduced pressure and add mixture to 2, 10g SCX columns, wash with MeOH, and elute with 1.0 N NH₃ in MeOH.Concentrate to afford 2.91 g, 10.8 mmol (71% yield) of the titlecompound as a white foam: ¹H NMR (500 MHz, DMSO-d₆): 2.9-3.1 (2H, m),3,2-3.5 (2H, m), 4.2-4.4 (2H, m), 6.9-7.2 (3H, m), 7.2-7.4 (1H, m),7.4-7.6 (1H, m), 7.9-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.7 (1H, m),8.2-9.4 (2H, m); MS m/z 269 (M+1).

EXAMPLE 5796-(2-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-nicotinamide

Combine 6-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-nicotinamide (46.9mg, 0.17 mmol), DMF (3 mL), Et₃N (0.1 mL, 0.77 mmol), andphenethylbromide (52 uL, 0.38 mmol) in a 7 mL vial. Place the reactionvial on a shaker at 70° C. for 72 hours, and then add water and ethylacetate. Wash the ethyl acetate layer several times with water, 10%LiCl, and dry over Na₂SO₄. Concentrate organic mixture and flashchromatograph using 30% THF, 4% 1.0 N NH₃ in MeOH, 76% CH₂Cl₂ to afford23.2 mg, (37% yield) of the title compound: MS m/z 374 (M+1).

By the method of example 579 the following compounds were prepared andisolated as the free base:

Name of the Final No.: X′ Compound Data 580 Benzyl 6-(2-Benzyl-1,2,3,4-Mass spectrum (ion spray): tetrahydro-isoquinoline-6- m/z = 360 (M + 1);¹H NMR (500 yloxy)-nicotinamide MHz, (CDCl₃) 2.7-3.0(4H, m), 3.6-3.8(4H,m), 6.8-7.1(3H, m), 7.2-7.5(4H, m), 8.1-8.2(1H, m), 8.5-8.7(1H, s) 581Pentyl 6-(2-Pentyl-1,2,3,4- Mass spectrum (ion spray):tetrahydro-isoquinolin-6- m/z = 340 (M + 1); ¹H NMR (500yloxy)-nicotinamide MHz, (CDCl₃) 0.8-1.0(3H, m), 1.2-1.4(4H, m),1.5-1.7(2H, m), 2.4-2.6(2H, m), 2.7-2.8(2H, m), 2.8-3.0(2H, m),3.6-3.7(2H, m), 5.8-6.3(1H, br d), 6.8-7.1(4H, m), 8.1-8.2(1H, m),8.5-8.7(1H, s) 582 2-1H-Indol-3-yl-ethyl] 6-[2-(2-1H-Indol-3-yl- Massspectrum (ion spray): ethyl)-1,2,3,4-tetrahydro- m/z = 413 (M + 1);isoquinolin-6-yloxy]- nicotinamide 583 2-(3-Chloro-benzyl)6-[2-(3-Chloro-benzyl)- Mass spectrum (ion spray): 1,2,3,4-tetrahydro-m/z = 394 (M + 1) isoquinoline-6-yloxy]- nicotinamide 5842-(2-Carbamoyl-ethyl) 6-[2-Carbamoyl-ethyl)- Mass spectrum (ion spray):1,2,3,4-tetrahydro- m/z = 341 (M + 1); isoquinolin-6-yloxy]-nicotinamide 585 2-(2-Phenylsulfanyl-ethyl) 6-[2-(2-Phenylsulfanyl- Massspectrum (ion spray): ethyl)-1,2,3,4-tetrahydro- m/z = 406isoquinolin-6-yloxy]- (M + 1); nicotinamide 586 2-(3-Methyl-butyl)6-[2-(3-Methyl-butyl)- Mass spectrum (ion spray): 1,2,3,4-tetrahydro-m/z = 340 (M + 1); isoquinolin-6-yloxy]- nicotinamide 5872-(4-Trifluoromethyl- 6-[2-(4-Trifluoromethyl]- Mass spectrum (ionspray): enzyl) benzyl)-1,2,3,4-tetrahydro- m/z = 428 (M + 1);isoquinolin-6-yloxy]- nicotinamide 588 2-(3-Chloro-benzyl)6-[2-(3-Chloro-benzyl)- Mass spectrum (ion spray): 1,2,3,4-tetrahydro-m/z = 394 (M + 1); isoquinolin-6-yloxy]- nicotinamide 5892-(3-Phenyl-allyl) 6-[2-(3-Phenyl-allyl)- Mass spectrum (ion spray):1,2,3,4,-tetrahydro- m/z = 386 (M + 1); isoquinolin-6-yloxy]-nicotinamide 590 2-(5-Chloro- 6-[2-(5-Chloro- Mass spectrum (ion spray):benzo[b]thiophen-3- benzo[b]thiophen-3- m/z = 450 (M + 1) ylmethyl]ylmethyl-1,2,3,4- tetrahydro-isoquinolin-6- yloxy)-nicotinamide 5912-Cyclopropylmethyl] 6-(2-Cyclopropylmethyl- Mass spectrum (ion spray):1,2,3,4-tetrahydro- m/z = 324 (M + 1); isoquinolin-6-yloxy)-nicotinamide 592 2-(3,5-Bis-trifluoromethyl- 6-[2-(3,5-Bis- Massspectrum (ion spray): benzyl) trifluoromethyl-benzyl)- m/z = 496 (M +1); 1,2,3,4-tetrahydro- isoquinolin-6-yloxy]- nicotinamide 5932-(3-Bromo-benzyl) 6-[2-(Bromo-benzyl)- Mass spectrum (ion spray):1,2,3,4-tetrahydro- m/z = 438 (M); isoquinolin-6-yloxy]- nicotinamide594 2-(4-Methyl-benzyl) 6-[2-Methyl-benzyl)- Mass spectrum (ion spray):1,2,3,4-tetrahydro- m/z = 374 (M + 1); isoquinolin-6-yloxyl]-nicotinamide 595 2-(2-Fluoro-benzyl) 6-[2-(2-Fluoro-benzyl)- Massspectrum (ion spray): 1,2,3,4-tetrahydro- m/z = 378 (M + 1);isoquinolin-6-yloxyl]- nicotinamide 596 2-(3-Methoxy-benzyl)6-[2-(3-Methoxy-benzyl)- Mass spectrum (ion spray): 1,2,3,4-tetrahydro-m/z = 390 (M + 1); isoquinolin-6-yloxy]- nicotinamide 5972-(1H-Benzoimidazol- 6-[2-(1H-Benzoimidazol-2- Mass spectrum (ionspray): 2-ylmethyl) ylmethyl)-1,2,3,4- m/z = 400 (M + 1);tetrahydro-isoquinolin-6- yloxy]-nicotinamide 598 2-(5-Chloro-6-[2-(5-Chloro-thiophen-2- Mass spectrum (ion spray):thiophen-2-ylmethyl) ylmethyl)-1,2,3,4- m/z = 400tetrahydro-isoquinolin-6- (M + 1); yloxy]-nicotinamide 5992-(2,6-Dichloro-benzyl) 6-[2-(2,6-Dichloro-benzyl)- Mass spectrum (ionspray): 1,2,3,4-tetrahydro- m/z = 428 (M); isoquinolin-6-yloxy]-nicotinamide 600 2-(3-Fluoro-benzyl) 6-[2-(3-Fluoro-benzyl)- Massspectrum (ion spray): 1,2,3,4-tetrahydro- m/z = 378isoquinolin-6-yloxyl]- (M + 1); nicotinamide 601 2-[2-(4-Methoxy-6-{2-[2-(4-Methoxy- Mass spectrum (ion spray): phenyl)-ethyl]phenyl)-ethyl]-1,2,3,4- m/z = 404 tetrahydro-isoquinolin-6- (M + 1);yloxy}-nicotinamide 602 3-Propionic acid 3-[6-(5-Carbamoyl- Massspectrum (ion spray): pyridin-2-yloxy)-3,4- m/z = 342dihydro-1H-isoquinolin- (M + 1); 2-yl]-propionic acid 6032-(3-Piperidin- 6-[2-(3-Piperidin-1-yl- Mass spectrum (ion spray):1-yl-propyl) propyl)-1,2,3,4-tetrahydro- m/z = 395isoquinolin-6-yloxyl]- (M + 1); nicotinamide 604 2-Pent-4-ynyl6-(2-Pent-4-ynly-1,2,3,4- Mass spectrum (ion spray):tetrahydro-isoquinolin-6- m/z = 336 yloxy)-nicotinamide (M + 1); 6052-(2-Piperidin- 6-[2-(2-Piperidin-1-yl- Mass spectrum (ion spray):1-yl-ethyl) ethyl)-1,2,3,4-tetrahydro- m/z = 381 isoquinolin-6-yloxy]-(M + 1); nicotinamide 606 2-(2-Diisopropyl- 6-[2-(2-Diisopropylamino-Mass spectrum (ion spray): amino-ethyl) ethyl)-1,2,3,4-tetrahydro- m/z =397 isoquinolin-6-yloxy]- (M + 1); nicotinamide 6072-(3,3,4,4-Tetrafluoro- 6-[2-(3,3,4,4,-Tetrafluoro- Mass spectrum (ionspray): butyl) butyl)-1,2,3,4,-tetrahydro- m/z = 398isoquinolin-6-yloxy]- (M + 1); nicotinamide 608 2-Cyclobutylmethyl6-(2-Cyclobutylmethyl- Mass spectrum (ion spray): 1,2,3,4-tetrahydro-m/z = 338 isoquinolin-6-yloxyl)- (M + 1); nicotinamide 6092-(3,3-Dimethyl-butyl) 6-[2-(3,3-Dimethyl-butyl)- Mass spectrum (ionspray): 1,2,3,4-tetrahydro- m/z = 354 isoquinolin-6-yloxy]- (M + 1);nicotinamide 610 2-(3,4,4-Trifluoro- 6-[2-(3,4,4-Trifluoro-but-3- Massspectrum (ion spray): but-3-enyl) enyl)-1,2,3,4-tetrahydro- m/z = 378isoquinolin-6-yloxy]- (M + 1); nicotinamide 611 2-(2-Methoxy-benzyl)6-[2-(2-Methoxy-benzyl)- Mass spectrum (ion spray): 1,2,3,4- m/z = 390tetrahydroisoquinolin-6- (M + 1); yloxy]-nicotinamide 6122-Pyridin-3-ylmethyl 6-(2-Pyridin-3-ylmethyl- Mass spectrum (ion spray):1,2,3,4-tetrahydro- m/z = 361 isoquinolin-6-yloxyl)- (M + 1);nicotinamide

Intermediate 9A [2-(3-Methoxy-phenyl)-ethyl]-carbamic acid methyl ester

Combine 2-(3-methoxyphenyl)ethylamine (9.6 mL, 66.1 mmol), THF (300 mL),Et₃N (11.0 mL, 78.9 mmol), and methyl chloroformate (26.0 mL, 339 mmol)at 0° C. under nitrogen atmosphere. Stir at room temperature for 18hours, add the mixture into water, wash with brine, and dry the organiclayer over Na₂SO₄ followed by concentrating under reduced pressure.Flash chromatograph using 2:1 hexanes:ethyl acetate to afford 13.6 g,65.0 mmol (98% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃);2.8 (2H, t, J=6.7, 7.0 Hz), 3.41-3.46 (2H, m), 3.7 (3H, s), 3.8 (3H, s),4.6-4.8 (1H, br s), 6.7-6.8 (3H, m), 7.2-7.3 (1H, m); MS m/z 210 (M+1).

Intermediate 10A 8-Methoxy-3,4-dihydro-2H-isoquinolin-1-one

Combine polyphosphoric acid (30 g) at 180° C. and[2-(3-methoxy-phenyl)-ethyl]-carbamic acid methyl ester (3.0 g, 14.33mmol). Stir for 15 minutes then add to a beaker of ice. Extract theproduct from the water using CH₂Cl₂ and CHCl₃. Dry the organic layerover Na₂SO₄ and then concentrate under reduced pressure. Flashchromatograph using 5% MeOH in ethyl acetate to afford 0.340 g, 1.92mmol (13% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 2.92(2H, t, J=6.4 Hz), 3.43-3.47 (2H, m), 3.85 (3H, s), 6.2-6.3 (1H, br s),6.8-6.9 (2H, m), 7.3-7.4 (1H, m), 7.5-7.6 (2H, m); MS m/z 178 (M+1).

Intermediate 11A 8-Methoxy-1,2,3,4-tetrahydro-isoquinoline

Combine 8-methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.778 g, 4.40 mmol),THF (20 mL), and LiAlH₄ (0.333 g, 8.8 mmol) at 0° C. under nitrogenatmosphere. After 30 minutes of the reaction, reflux for 2 hours andthen cool to room temperature. Quench the reaction by adding water and1.0 M NaOH at 0° C. and stirring for 12 hours at room temperature.Filter the reaction through Celite® and elute with THF. Afterconcentrating the filtrate under reduced pressure, add the mixture to a10 g SCX column pre-treated with 5% AcOH/MeOH. After rinsing severaltimes with MeOH, elute the product using 1.0 N NH₃-MeOH followed byconcentration under reduced pressure to afford 0.665 g, 4.07 mmol (93%yield) of the title compound as a tan oil: ¹H NMR (500 MHz, CDCl₃);1.7-2.0 (1H, b s), 2.77 (2H, t, J=5.86 Hz), 3.09 (2H, t, J=5.86 Hz), 3.8(3H, s), 3.95 (2H, s), 6.6-6.8 (2H, m), 7.0-7.15 (1H, m); TLC 5%MeOH:ethyl acetate R_(f):=0.1

Intermediate 12A 1,2,3,4-Tetrahydro-isoquinolin-8-ol

Combine 8-methoxy-tetrahydroisoquinoline (665.7 mg, 4.08 mmol) and 48%HBr at room temperature. Reflux the reaction for 3 hours and then coolto room temperature. Recrystallize the product from EtOH and diethylether to afford 754.2 mg, 3.28 mmol (80% yield) of the title compound asa tannish white solid: ¹H NMR (500 MHz, DMSO-d₆); 2.9 (2H, t, J=6.16,5.86 Hz), 3.2-3.4 (2H, m), 4.0 (2H, s), 6.6-6.8 (2H, m), 7.0-7.1 (1H,m), 8.8-9.1 (2H, br m), 9.9 (1H, s); MS m/z 148 (M−1).

Intermediate 13A 8-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine 8-hydroxy tetrahydroisoquinoline HBr salt (754.2 mg, 3.28 mmol),and Et₃N (2.8 mL, 19.68 mmol), anhydrous THF (20 mL), and BOC-anhydride(1.14 g, 3.94 mmol). Stir the reaction at room temperature for 72 hoursfollowed by an aqueous work-up. Wash the organic layer with brine anddry over Na₂SO₄. After concentrating the organic layer under reducedpressure, flash chromatograph using 4:1 hexanes:ethyl acetate eluent toafford 249.6 mg, 1.01 mmol (31% yield) of the title compound as a whitefoam: ¹H NMR (500 MHz, CDCl₃); 1.5 (9H, s), 2.73-2.79 (2H, m), 3.5-3.6(2H, m), 4.45-4.61 (2H, b s), 6.6-6.9 (2H, m), 6.9-7.2 (1H, m); TLC 4:1hexanes:ethyl acetate R_(f):=0.13

Intermediate 14A8-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine in a 100 mL round bottom flask equipped with a stir bar, a DeanStark trap, and a reflux condenser8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(249.6 mg, 1.01 mmol), dimethylacetamide (30 mL), toluene (10 mL), K₂CO₃(814.74 mg, 5.90 mmol), and 6-chloronicatinamide (626.28 mg, 4.0 mmol).Reflux the reaction under nitrogen for 5 hours. After cooling to roomtemperature, add water to the reaction mixture and extract the productusing ethyl acetate. Wash the organic layer with brine and dry overNa₂SO₄. After concentrating under reduced pressure, flash chromatographusing 20% THF in CH₂Cl₂ to afford 245.1 mg, 0.66 mmol (66% yield) of thetitle compound: ¹H NMR (500 MHz, CD₃OD); 1.3-1.5 (9H, m), 2.8-2.9 (2H,m), 3.5-3.7 (2H, m), 3.85 (2H, s), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m),7.2-7.3 (1H), m), 7.5-7.6 (1H, m), 8.2-8.3 (1H, m), 8.6-8.7 (1H, br s),8.8 (1H, s); MS m/z 370 (M+1).

Intermediate 15A 6-(1,2,3,4-Tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Combine8-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (249.6 mg, 1.01 mmol), CH₂Cl₂ (25 mL), and TFA (10mL) at room temperature under nitrogen atmosphere. Stir for 12 hoursthen concentrate under reduced pressure. Solubilize the mixture in MeOHand add to a 2 g SCX Column (pre-treated with 5% AcOH-MeOH), washseveral times with MeOH, and elute with 1.0 N NH₃ in MeOH to afford156.1 mg, 0.58 mmol (57% yield) of the title compound.

EXAMPLE 6136-(2-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 24, using phenethylbromide (40 uL,0.28 mmol) gives 26.9 mg (55% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.8-2.1 (4H, m), 2.7-3.0 (6H, m), 5.9-6.3 (2H, br d),6.8-7.4 (10H, m), 8.1-8.3 (1H, m), 8.5 (1H, s); MS m/z 374 (M+1).

EXAMPLE 6146-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 24, using benzylbromide (0.1 mL, 0.97mmol) gives 45.6 mg (63% yield) of the title compound.

EXAMPLE 6156-(2-Pentyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 24, using pentylbromide (54 uL, 0.48mmol) gives 32.5 mg (48% yield) of the title compound: ¹H NMR (500 MHz,CD3OD); 0.8 (3H, t), 1.2-1.3 (4H, m), 1.4-1.6 (2H, m), 2.3-2.5 (2H, m),2.7 (2H, t), 2.9-3.0 (2H, m), 3.5 (2H, s), 6.8-7.2 (5H, m), 8.1-8.2 (1H,m), 8.6 (1H, s); MS m/z 340 (M+1).

Intermediate 16A 1,2-Bis-bromomethyl-4-methoxy-benzene

Combine 3,4-dimethylanisole (2.72 g, 20.0 mmol). CCl₄ (50 mL), NBS (7.12g, 40.0 mmol), and benzoyl peroxide (40.0 mg, 0.17 mmol). Reflux tiereaction for 12 hours and then cool to room temperature and concentrateunder reduced pressure. Flash chromatograph using 4:1 CHCl₃:hexaneseluent to afford 1.90 g, 6.4 mmol (32% yield) of the title compound: ¹HNMR (500 MHz, CDCl₃); 3.8 (3H, s), 4.6 (2H, s), 4.7 (2H, s), 6.8-6.9(2H, m), 7.1-7.4 (1H, m); TLC 4:1 CHCl₃:hexanes R_(f):=0.67

Intermediate 17A 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindol

Combine in a round bottom flask 1,2-bis-bromomethyl-4-methoxy-benzene(1.0 g, 3.40 mmol), benzyltriethylammonium chloride (73.5 mg, 3.2 mmol),50% NaOH (aq)/toluene (3.0 mL/14 mL), and then drop wise add benzylamine(0.37 mL, 3.39 mmol). Stir the reaction at room temperature for 3 hours,add to ethyl acetate, wash with water, brine, and dry over Na₂SO₄. Afterconcentrating under reduced pressure, add the mixture to a 10 g SCXcolumn, wash with MeOH, and elute with 1.0 N NH₃-MeOH. Flashchromatograph using 3:1 hexanes:ethyl acetate to afford 580.0 mg, 2.42mmol (71% yield) of the title compound as a brown oil: ¹H NMR (500 MHz,CDCl₃); 3.7 (3H, s), 3.9-4.0 (6H, m), 6.7-6.8 (2H, m), 7.1 (1H, d),7.3-7.5 (5H, m); MS m/z 238 (M−1).

Intermediate 18A 2-Benzyl-2,3-dihydro-1H-isoindol-5-ol

Combine 2-benzyl-5-methoxy-2,3-dihydro-1H-isoindol (580.0 mg, 2.42 mmol)and 48% HBr (aq) (20 mL). Reflux the reaction for 5 hours and then coolto room temperature. Concentrate the reaction mixture under reducedpressure then add to 5 g SCX column. Wash the column with MeOH and elutewith 1.0 N NH₃-MeOH to afford 265.4 mg, 1.17 mmol (49% yield) of thetitle compound as a brown solid: ¹H NMR (500 MHz, CD₃OD); 3.8-3.9 (4H,m), 3.91 (2H, s). 6.6-6.7 (2H, m), 7.0 (1H, d), 7.2-7.5 (5H, m); MS m/z226 (M+1).

EXAMPLE 616 6-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide

Combine in a round bottom flask equipped with a stir bar and a DeanStark trap under a nitrogen atmosphere2-benzyl-2,3-dihydro-1H-isoindol-5-ol (265.4 mg, 1.18 mmol), toluene (10mL), DMA (30 mL), K₂CO₃ (244.6 mg, 1.77 mmol), and 6-chloronicatinamide(184.4 mg, 1.18 mmol). Reflux the reaction for 6 hours and then cool toroom temperature. Add ethyl acetate, wash the ethyl acetate layerseveral times with water, brine, and dry over Na₂SO₄. Afterconcentrating under reduced pressure, purify the mixture by reversephase chromatography (5% to 95% (0.01% TFA buffer inacetonitrile)/water) to afford 333.4 mg, 0.97 mmol (82% yield) of thetitle compound as a white foam: ¹H NMR (500 MHz, CD₃OD); 4.6-4.8 (6H,m), 7.0 (1H, d), 7.1-7.2 (2H, m), 7.4-7.6 (6H, m), 8.2 (1H, d), 8.6 (1H,s); MS m/z 346 (M+1).

Intermediate 19A 6-(2,3-Dihydro-1H-isoindol-5-yloxy)-nicotinamide

Combine 6-(2-benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0mg, 0.67 mmol), EtOH (5 mL), and 10% Pd—C (45.0 mg) and place under ahydrogen balloon. Stir the reaction at room temperature for 168 hours atatmospheric pressure. Filter the reaction mixture through a pad ofCelite® using MeOH eluent and then concentrate the filtrate underreduced pressure. Add the mixture to a 2 g SCX column, wash with MeOH,and elute using 1.0 N NH₃-MeOH. After concentrating under reducedpressure, purify the mixture by flash chromatography using 10% 1.0 NNH₃-MeOH/DCM eluent to afford 19.2 mg, 0.08 mmol (11% yield) of thetitle compound as a white solid: ¹H NMR (500 MHz, CD₃OD); 4.1-4.3 (4H,br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H, m), 8.2-8.3 (1H, m), 8.6 (1H, s);MS m/z 254 (M−1).

EXAMPLE 617 6-(2-Phenethyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide

Combine 6-(2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (19.2 mg, 0.08mmol), DMF (3 mL), Et₃N (46 uL, 0.33 mmol), and 2-phenethylbromide (23uL, 0.165 mmol). Place the reaction on a shaker for 12 hours at 70° C.,then cool to room temperature and concentrate under reduced pressure.Add the mixture to a 2 g SCX column, wash with MeOH, and then elute with1.0 N NH₃-MeOH. After concentrating the mixture, purify using reversephase chromatography (5% to 95% (0.001% TFA buffer inacetonitrile)/water) to afford 9.5 mg, 0.03 mmol (33% yield) of thetitle compound: ¹H NMR (500 MHz, CD₃OD); 2.8-3.2 (4H, m), 4.1-4.2 (4H,m), 6.8-7.1 (3H, m), 7.2-7.4 (6H, m), 8.2 (1H, d), 8.6 (1H, s); MS m/z358 (M−1).

EXAMPLES 618-636

EXAMPLE 6185-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine 5-hydroxy, 3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (2.0 g, 8 mmol), cesium carbonate (5.2 g, 16 mmol) andN,N-dimethylformamide (60 mL), stir at room temperature for 30 minutes.Add 6-chloronicotinamide (1.2 g, 8 mmol) and heat at 100° C. for 2 days.Cool to room temperature, dilute with brine, and then extract with ethylacetate (3×150 mL). Dry the ethyl acetate extracts with sodiumchloride/magnesium sulfate, filter, then concentrate on a rotaryevaporator to yield 3 g of the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with 0.5%conc. ammonium hydroxide/5% ethanol in chloroform to yield5-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (2.1 g, 5.7 mmol): ¹H NMR (DMSO-d₆, 300.00 MHz):8.54 (s, 1H); 8.30-8.23 (m, 1H); 8.02-7.93 (m, 1H); 7.48 (s, 1H); 7.23(d, 1H); 7.09-6.95 (m, 1H); 4.54 (s, 2H); 3.48-3.36 (m, 4H); 2.87-2.71(m, 2H); 1.39 (s, 9H).

EXAMPLE 619 6-(1,2,3,4-Tetrahydro-isoquinolin-5-yloxy)-nicotinamide

Add drop wise via an addition funnel a solution of trifluoroacetic acid(5.7 mL) in dichloromethane (25 mL) to a stirred solution of5-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (2.1 g, 5.7 mmol) in dichloromethane (75 mL) at 0°C. Warm to room temperature and stir for 18 hours. Evaporate on a rotaryevaporator, dissolve the residue in methanol (50 mL) and dichloromethane(50 mL), and then add MP-carbonate resin (7.9 g @ 2.87 eq/g). Agitatefor 2 hours, filter, concentrate on a rotary evaporator, and dry undervacuum to yield 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide(1.5 g, 5.6 mmol): HPLC=85% (50/50 to 90/10 ACN/(0.1% TFA in water),Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm). ¹H NMR (DMSO-d₆,300.00 MHz): 8.55 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H),6.95 (m, 5H), 3.90 (s, 2H), 2.85 (m, 2H), 2.38 (m, 2H),

EXAMPLE 6206-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide

Combine 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (100 mg,0.3 7 mmol), benzaldehyde (39 μL, 0.38 mmol), sodiumtriacetoxyborohydride (101 mg, 0.48 mmol), acetic acid (22 μL, 0.39mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for18 hours. Dilute the reaction with saturated aqueous sodium bicarbonatesolution and extract with dichloromethane (3×25 mL). Dry the combineddichloromethane extracts with sodium chloride/magnesium sulfate, filter,and concentrate on a rotary evaporator to yield 45 mg of the crudeproduct. The crude product is purified by flash column chromatography onsilica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to(1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield6-(2-benzyl-1,2,3,4-tetralhydroisoquinolin-5-yloxy)-nicotinamide (31 mg,0.09 mmol): m/z=360.1 (M+1); ¹H NMR (DMSO-d₆, 300.00 MHz): 8.56 (s, 1H);8.16-8.12 (m, 1H); 7.38-7.15 (m, 6H); 6.94-6.89 (m, 3H); 6.17 (s, 2H);3.74-3.61 (m, 4H); 2.69-2.66 (m, 4H), HPLC=99% (30/70 to 90/10 ACN/(0.1%TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).

By the method of Example 620 the following compounds were prepared andisolated as the free base except where noted:

Data HPLC (30/70 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6mm × 15 cm × 5 micron, λ = 254 nm) Mass spectrum Retention Exam- (ionspray): Time ple Name m/z (M + 1) Purity (minutes) 6216-(2-Butyl-1,2,3,4- 326.16 96 2.55 tetrahydro-isoquinolin-5-yloxy)-nicotinamide 622 6-[2-(3-Methyl-butyl)- 340.17 99 3.161,2,3,4-tetrahydro- isoquinolin-5-yloxy]- nicotinamide 6236-(2-Thiophen-2- 366.07 99 2.57 ylmethyl-1,2,3,4-tetrahydro-isoquinolin-5- yloxy)-nicotinamide 6246-(2-Phenethyl-1,2,3,4- 374.14 100 4.19 tetrahydro-isoquinolin-5-yloxy)-nicotinamide 625 6-(2-Hexyl-1,2,3,4- 354.2 94tetrahydro-isoquinolin-5- yloxy)-nicotinamide 6266-(2-Isopropyl-1,2,3,4- 312.13 60 tetrahydro-isoquinolin-5-yloxy)-nicotinamide 627 6-(2-Propyl-1,2,3,4- 312.15 71 1.94tetrahydro-isoquinolin-5- yloxy)-nicotinamide 628 6-(2-Isobutyl-1,2,3,4-326.15 98 2.15 tetrahydro-isoquinolin-5- yloxy)-nicotinamide 6296-(2-Pentyl-1,2,3,4- 340.17 99 3.20 tetrahydro-isoquinolin-5-yloxy)-nicotinamide 630 6-(2-Furan-2-ylmethyl- 350.11 98 2.171,2,3,4-tetrahydro- isoquinolin-5-yloxy)- nicotinamide 6316-(2-Cyclohexyl-1,2,3,4- 352.16 96 2.76 tetrahydro-isoquinolin-5-yloxy)-nicotinamide 632 6-(2-Pyridin-2-ylmethyl- 361.13 76 1.951,2,3,4-tetrahydro- isoquinolin-5-yloxy)- nicotinamide 6336-(2-Pyridin-3-ylmethyl- 361.13 99 1.53 1,2,3,4-tetrahydro-isoquinolin-5-yloxy)- nicotinamide 634 6-(2-Pyridin-4-ylmethyl- 361.1399 1.57 1,2,3,4-tetrahydro- isoquinolin-5-yloxy)- nicotinamide 6356-(2-Cyclohexylmethyl- 366.18 94 4.19 1,2,3,4-tetrahydro-isoquinolin-5-yloxy)- nicotinamide 636 6-[2-(3-Phenyl-propyl)- 388.16 945.60 1,2,3,4-tetrahydro- isoquinolin-5-yloxy]- nicotinamide

EXAMPLE 6377-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (1.7 g, 6.8 mmol, Reference J. Med. Chem. 1998, 41(25), 4983-4994), cesium carbonate (4.4 g, 13.6 mmol) andN,N-dimethylformamide (75 mL) and stir at room temperature for 30minutes. Add 6-chloronicotinamide (1.1 g, 6.8 mmol) and heat at 100° C.for 2 days. Cool to room temperature, dilute with brine then extractwith ethyl acetate (3×125 mL). Dry the ethyl acetate extracts withsodium chloride/magnesium sulfate, filter, then concentrate on a rotaryevaporator to yield 12 g of the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with (0.1%conc. ammonium hydroxide/1% ethanol) to (1% conc. ammonium hydroxide/10%ethanol) in chloroform to yield7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.2 g, 3.3 mmol): ¹H NMR (CDCl₃, 300.00 MHz):8.59 (s, 1H); 8.17 (d, 1H); 7.20-7.17 (m, 2H); 6.98-6.89 (m, 2H) 2H);4.57 (s, 2H); 3.68-3.66 (m, 2H); 2.83 (t, 2H); 1.48 (s, 9H).

EXAMPLE 638 6-(1,2,3,4-Tetrahydro-isoquinolin-7-yloxy)-nicotinamide

Add drop wise via an addition funnel a solution of trifluoroacetic acid(3.3 mL) in dichloromethane (10 mL) to a stirred solution of7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.2 g, 3.3 mmol)) in dichloromethane (50 mL) at0° C. Warm to room temperature and stir for 18 hours. Evaporate on arotary evaporator, dissolve the residue in methanol, and then apply inequal parts to 2-10 g SCX cartridges. Wash each cartridge with methanoluntil neutral pH then elute product with 2.0 M ammonia in methanol.Collect the basic eluent and concentrate on a rotary evaporator to yield6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (0.9 g, 3.3mmol): ¹H NMR (CDCl₃, 300.00 MHz): 8.57 (s, 1H); 8.15 (d, 1H); 7.15-7.13(m, 1H); 6.96-6.89 (m, 2H); 6.80 (s, 1H); 5.87 (br, 2H); 4.01 (s, 2H);3.17-3.13 (m, 2H); 2.82-2.78 (m, 2H); 1.73 (br, 1H).

EXAMPLE 6396-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide

Combine 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (94 mg,0.35 mmol), benzaldehyde (37 μL, 0.37 mmol), sodiumtriacetoxyborohydride (96 mg, 0.46 mmol), acetic acid (21 μL, 0.37mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for18 hours. Dilute the reaction with saturated aqueous sodium bicarbonatesolution and extract with 5% methanol in dichloromethane (3×25 mL). Drythe combined 5% methanol in dichloromethane extracts with sodiumchloride/magnesium sulfate, filter, and concentrate on a rotaryevaporator to yield 100 mg of the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with 1%conc. ammonium hydroxide/10% ethanol in chloroform to yield6-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide 2039910(30 mg, 0.09 mmol): m/z=360.12 (M+1); ¹H NMR (CDCl₃, 300.00 MHz): 8.50(d, 1H); 8.09-8.05 (m, 1H); 7.34-7.20 (m, 5H); 7.09 (d, 1H); 6.87-6.82(m, 2H); 6.71 (d, 1H); 5.80 (s, 2H); 3.63-3.57 (m, 4H); 2.87-2.69 (m,4H), HPLC=96% @ 2.98 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).

By the method of Example 639 the following compounds were prepared andisolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm × 15 cm × 5 micron, Mass λ = 254 nm) spectrum RetentionExam- (ion spray): Time ple Name m/z (M + 1) Purity (minutes) 6406-(2-Propyl-1,2,3,4- 312.1 94 6.08 tetrahydro-isoquinolin-7-yloxy)-nicotinamide 641 6-(2-Cyclohexyl-1,2,3,4- 352.1 96 6.32tetrahydro-isoquinolin-7- yloxy)-nicotinamide 6426-[2-(3-Cyclohexyl-propyl)- 394.2 90 6.84 1,2,3,4-tetrahydro-isoquinolin-7-yloxy]- nicotinamide 643 6-(2-Pentyl-1,2,3,4- 340.1 966.38 tetrahydro-isoquinolin-7- yloxy)-nicotinamide 6446-(2-Cyclohexylmethyl- 366.1 98 6.45 1,2,3,4-tetrahydro-isoquinolin-7-yloxy)- nicotinamide 645 6-(2-Phenethyl-1,2,3,4- 374.1 966.46 tetrahydro-isoquinolin-7- yloxy)-nicotinamide 6466-[2-(3-Phenyl-propyl)- 388.1 99 6.53 1,2,3,4-tetrahydro-isoquinolin-7-yloxy]- nicotinamide 647 6-(2-Pyridin-3-ylmethyl- 361.1 995.8 1,2,3,4-tetrahydro- isoquinolin-7-yloxy)- nicotinamide 6486-(2-Thiophen-2-ylmethyl- 366 99 6.24 1,2,3,4-tetrahydro-isoquinolin-7-yloxy)- nicotinamide 649 6-(2-Furan-2-ylmethyl- 350.1 966.14 1,2,3,4-tetrahydro- isoquinolin-7-yloxy)- nicotinamide 6506-[2-(3-Chloro-benzyl)- 394 98 6.47 1,2,3,4-tetrahydro-isoquinolin-7-yloxy]- nicotinamide

EXAMPLE 6516-{2-Methyl-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 2-Methyl-4-(2-nitro-vinyl)-phenol

The 2-methyl-4-hydroxy-benzaldehyde (980 mg, 6.3 mmol), nitromethane(2.0 mL, 37.7 mmol) and ammonium acetate (1.9 g, 25.1 mmol) weredissolved in acetic acid (9 mL) and the reaction heated at 110° C. for 2h. The reaction is concentrated under reduced pressure and the residuepartitioned between ether and water. Separate the layers and dry withNa₂SO₄, filter and concentrate under reduced pressure. Purify the crudeby flash chromatography (eluent: EtOAc/hexane 20/80 and 30/70) affordedthe title compound (1.0 g). ¹H-NMR (CDCl₃, 200 MHz): 7.94 (d, 1H, J=13.4Hz), 7.50 (d, 1H, J=13.6 Hz), 7.34-7.27 (m, 2H), 6.82 (d, 1H, J=8.1 Hz),2.28 (s, 3H).

Step 2 4-(2-Amino-ethyl)-2-methyl-phenol

Procedure 1: Dissolve compound obtained in step 1 above (440 mg, 2.46mmol) in methanol (10 mL) and add Pd/C 10% (272 mg) and HCl conc (1 mL).Stir the mixture at room temperature under hydrogen overnight. Filtrateover celite and eliminate the solvent. Purify by SCX column to obtainthe title compound (232 mg, 63%).

Procedure 2: To lithium aluminum hydride 1.0 M in ether (1.67 mL, 1.67mmol) at 0° C. a solution of aluminum trichloride (224 mg, 1.67 mmol) inTHF (2 mL) is added. After 5 min a solution of compound obtained in step1 above (100 mg, 0.56 mmol) in THF (2 mL) is added and the reaction isallowed to stir at room temperature overnight. Add water and then 3 NHCl, the aqueous layer is extracted with 3/1 n-butanol/toluene. Thecombined organic layers are dried over sodium sulfate and concentrated.SCX ion-exchange chromatography afforded 71 mg (84%) of the titlecompound. Electrospray MS M+1 ion=152. ¹H-NMR (methanol-d₄, 200 MHz):6.89 (bs, 1H), 6.82 (dd, 1H, J=8.3 and 2.4 Hz), 6.64 (d, 1H, J=8.1 Hz),2.80 (t, 2H, J=6.7 Hz), 2.61 (t, 2H, J=7.0 Hz), 2.15 (s, 3H).

Step 3 [2-(4-Hydroxy-3-methyl-phenyl)-ethyl]-carbamic acid tert-butylesther

Dissolve amine obtained in step 2 above (289 mg, 1.91 mmol) in dry THF(5 mL) under N₂ atmosphere, add a solution of di-tertbutyl dicarbonate(439 mg, 2.0 mmol) in THF (5 mL), stir the mixture at room temperatureovernight. Eliminate the solvent to obtain the title compound (462 mg,96%). TLC R_(f) (EtOAc/hexane 20/80): 0.27. ¹H-NMR (methanol-d₄, 200MHz): 6.88 (bs, 1H), 6.82 (d, 1H, J=8.3 Hz), 6.63 (d, 1H, J=8.1 Hz),3.17 (t, 2H, J=6.7 Hz), 2.60 (t, 2H, J=7.0 Hz), 2.14 (s, 3H), 1.50 (s,9H).

Step 4 {2-[4-(5-Cyano-pyridin-2-yloxy)-3-methyl-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (455 mg, 1.1 mmol),6-chloronicotinonitrile (251 mg, 1.81 mmol) and sodium hydride (87 mg,2.17 mmol) in DMSO (10 mL) is stirred at room temperature for 18 h. Pourthe mixture into iced water and extract the aqueous layer with EtOAc.Dry the organic layer over Na₂SO₄, filtrate and eliminate the solvent.Purify by flash chromatography (eluent: EtOAc/hexane 15/85 and 20/80) toget the title compound (358 mg, 57%). Electrospray MS M⁺+1-Boc groupion: 298. ¹H-NMR (CDCl₃, 200 MHz): 8.42 (dd, 1H, J=0.5 and 2.4 Hz), 7.90(dd, 1H, J=2.4 and 8.6 Hz), 7.11-6.94 (m, 4H), 3.37 (q, 2H, J=7.0 Hz),2.77 (t, 2H, J=7.2 Hz), 2.10 (s, 3H), 1.43 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-3-methyl-phenyl]-ethyl}-carbamicacid tert-butyl esther

The compound of step 4 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to formthe amide form nitrile have been described exhaustively somewhere inP-15876.

¹H-NMR (CDCl₃, 200 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=2.4 and8.6 Hz), 7.09-6.90 (m, 4H), 3.38 (q, 2H, J=6.7 Hz), 2.77 (t, 2H, J=7.0Hz), 2.11 (s, 3H), 1.43 (s, 9H).

Step 6 6-[4-(2-Amino-ethyl)-2-methyl-phenoxy]-nicotinamide

To a solution of compound of step 5 (376 mg, 1.01 mmol) in CH₂Cl₂ (20mL), trifluoroacetic acid is added (2.03 mL, 26.4 mmol). Stir thereaction mixture at room temperature for 2 h. Eliminate the solvent andpurify by SCX column to obtain the title compound (264 mg, 96%).Electrospray MS M⁺+1 ion: 272. ¹H-NMR (metanol-d₄, 200 MHz): 8.58 (d,1H, J=2.4 Hz), 8.24 (dd, 1H, J=2.7 and 8.9 Hz), 7.17-6.94 (m, 4H),2.94-2.86 (m, 2H), 2.78-2.71 (m, 2H), 2.10 (s, 3H).

Step 7

Combine 3-methyl-butylaldehyde (60 μl, 0.22 mmol), amine from step 6above (60 mg, 0.22 mmol) and 3 A molecular sieves (670 mg) in methanol(2 mL), stir the mixture at room temperature overnight. Add NaBH₄ (41mg, 1.10 mmol) and stir at room temperature for 3 hours. Filtrate themixture over celite and eliminate the solvent. Purify the crude mixtureby flash chromatography (eluent: CH₂Cl₂/MeOH 80/20) to obtain the titlecompound (45 mg, 60%). Electrospray MS M+1 ion=342. ¹H-NMR (metanol-d₄,200 MHz): 8.59 (dd, 1H, J=0.8 and 2.7 Hz), 8.24 (dd, 1H, J=2.4 and 8.6Hz), 7.19-7.10 (m, 2H), 7.00-6.93 (m, 2H), 2.93-2.76 (m, 4H), 2.70-2.62(m, 2H), 2.10 (s, 3H), 1.71-1.36 (m, 3H), 0.91 (d, 6H, J=6.4 Hz).

By the method of example 1 the following examples (examples 2-8) wereprepared. The purification process is described in each case

EXAMPLE 6526-{2-Methyl-4-[2-(3,3-dimethyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=356. ¹H-NMR(metanol-d₄, 200 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.24 (dd, 1H, J=2.4 and8.6 Hz), 7.18-7.10 (m, 2H), 7.00-6.94 (m, 2H), 2.92-2.78 (m, 4H),2.69-2.60 (m, 2H), 2.10 (s, 3H), 1.48-1.39 (m, 2H), 0.93 (s, 9H).

EXAMPLE 653 6-[2-Methyl-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/EtOAc/MeOH:NH₃ 2M35/60/5). Electrospray MS M+1 ion=342. ¹H-NMR (metanol-d₄, 200 MHz):8.59 (dd, 1H, J=0.5 and 2.3 Hz), 8.24 (dd, 1H, J=2.6 and 8.8 Hz),7.17-7.08 (m, 2H), 6.98-6.92 (m, 2H), 2.88-2.75 (m, 4H), 2.65-2.57 (m,2H), 2.09 (s, 3H), 1.59-1.25 (m, 6H), 0.91 (t, 3H, J=6.4 Hz).

EXAMPLE 6546-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-2-methyl-phenoxy}-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/MeOH 90/10).Electrospray MS M+1 ion=368. ¹H-NMR (metanol-d₄, 200 MHz): 8.59 (d, 1H,J=2.4 Hz), 8.24 (dd, 1H, J=2.7 and 8.6 Hz), 7.18-7.10 (m, 2H), 7.00-6.93(m, 2H), 2.85 (bs, 4H), 2.50 (d, 2H, J=6.4 Hz), 2.10 (s, 3H), 1.77-0.84(m, 11H).

EXAMPLE 6556-{4-[2-(3-Fluoro-benzylamino)-ethyl]-2-methyl-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=380. ¹H-NMR(metanol-d₄, 200 MHz): 8.59 (dd, 1H, J=0.5 and 2.4 Hz), 8.24 (dd, 1H,J=2.4 and 8.6 Hz), 7.38-6.92 (m, 8H), 3.79 (s, 2H), 2.82 (s, 4H), 2.09(s, 3H).

EXAMPLE 6566-{4-[2-(3-Fluoro-benzylamino)-ethyl]-2-methyl-phenoxy}-nicotinamide,mesylate salt

Example 655 (free amine of example 656) was dissolved in THF, thenmethanosulfonic acid was added (1.0 eq), the mixture was stirred for 1hour and the solvent eliminated to give the title compound. ElectrosprayMS M+1 ion=380. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (bs, 1H), 8.28 (dd,1H, J=1.4 and 8.7 Hz), 7.56-7.02 (m, 8H), 4.30 (s, 2H), 3.36 (t, 2H,J=7.3 Hz), 3.06 (t, 2H, J=7.3 Hz), 2.72 (s, 3H), 2.14 (s, 3H).

EXAMPLE 6576-(4-{2-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-ethyl}-2-methyl-phenoxy)-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH9/B═CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=378. ¹H-NMR (methanol-d₄, 200 MHz): 8.59 (d, 1H, J=2.6 Hz), 8.24(dd, 1H, J=2.4 and 8.6 Hz), 7.16-6.91 (m, 4H), 6.16-5.88 (m, 2H),2.81-1.81 (m, 9H), 2.09 (s, 3H), 1.65-0.99 (m, 3H), 0.57-0.48 (m, 1H).

EXAMPLE 6586-[4-(2-Cyclooctylamino-ethyl)-2-methyl-phenoxy]-nicotinamide

Purification: Flash chromatography (eluent: CH₂Cl₂/MeOH 70/30).Electrospray MS M+1 ion=382. ¹H-NMR (metanol-d₄, 200 MHz): 8.59 (d, 1H,J=2.4 Hz), 8.24 (dd, 1H, J=2.4 and 8.6 Hz), 7.18-6.92 (m, 4H), 2.95-2.77(m, 5H), 2.12 (m, 1H), 2.10 (s, 3H), 1.89-1.46 (m, 13H).

EXAMPLE 6596-{3-Chloro-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 3-Chloro-4-(2-nitro-vinyl)-phenol

The 3-chloro-4-hydroxy-benzaldehyde (980 mg, 6.3 mmol), nitromethane(2.0 mL 37.7 mmol) and ammonium acetate (1.9 g, 25.1 mmol) weredissolved in acetic acid (9 mL) and the reaction heated at 110° C. for 2h. The reaction is concentrated under reduced pressure and the residuepartitioned between ether and water. Separate the layers and dry withNa₂SO₄, filter and concentrate under reduced pressure. Purify the crudeby flash chromatography (eluent: EtOAc/hexane 20/80 and 30/70) affordedthe title compound (1.0 g, 80%). ¹H-NMR (CDCl₃, 200 MHz): 8.34 (d, 1H,J=13.4 Hz), 7.82 (d, 1H, J=13.4 Hz), 7.71 (d, 1H, J=8.6 Hz), 6.94 (d,1H, J=2.4 Hz), 6.80 (dd, 1H, J=2.4 and 8.6 Hz).

Step 2 4-(2-Amino-ethyl)-3-choloro-phenol

To lithium aluminum hydride 1.0 M in ether (1.50 mL, 1.50 mmol) at 0° C.a solution of aluminum trichloride (201 mg, 1.51 mmol) in THF (2 mL) isadded. After 5 min a solution of compound obtained in step 1 above (100mg, 0.50 mmol) in THF (2 mL) is added and the reaction is allowed tostir at room temperature overnight. Add water and then 3 N HCl, theaqueous layer is extracted with 3/1 n-butanol/toluene. The combinedorganic layers are dried over sodium sulfate and concentrated. SCXion-exchange chromatography afforded 70 mg (81%) of the title compound.Electrospray MS M+1 ion=172. ¹H-NMR (methanol-d₄, 200 MHz): 7.06 (d, 1H,J=8.3 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.65 (dd, 1H, J=2.4 and 8.3 Hz), 2.82(m, 4H).

Step 3 [2-(4-Hydroxy-2-chloro-phenyl)-ethyl]-carbamic acid tert-butylesther

Dissolve amine obtained in step 2 above (620 mg, 3.62 mmol) in dry THF(20 mL) and DMF (1 mL) under N₂ atmosphere, add a solution ofdi-tertbutyl dicarbonate (791 mg, 3.62 mmol) in THF (10 mL), stir themixture at room temperature overnight. Eliminate the solvent and purifythe crude by flash chromatography (eluent: EtOAc/hexane 30/70) to obtainthe title compound (670 mg, 68%). TLC R_(f) (EtOAc/hexane 20/80): 0.27.¹H-NMR (methanol-d₄, 200 MHz): 7.06 (d, 1H, J=8.3 Hz), 6.78 (d, 1H,J=2.6 Hz), 6.65 (dd, 1H, J=2.4 and 8.3 Hz), 3.21 (t, 2H, J=6.7 Hz), 2.78(t, 2H, J=7.5 Hz), 1.41 (s, 9H).

Step 4 {2-[4-(5-Cyano-pyridin-2-yloxy)-2-chloro-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (650 mg, 2.4 mmol),6-chloronicotinonitrile (333 mg, 2.4 mmol) and sodium hydride (115 mg,2.9 mmol) in DMSO (12 mL) is stirred at room temperature for 18 h. Pourthe mixture into iced water and extract the aqueous layer with EtOAc.Dry the organic layer over Na₂SO₄, filtrate and eliminate the solvent.Purify by flash chromatography (eluent: EtOAc/hexane 20/80 and 30/70) toget the title compound (810 mg, 90%). Electrospray MS M⁺+1-Boc groupion: 318. ¹H-NMR (CDCl₃, 200 MHz): 8.46 (dd, 1H, J=0.5 and 2.2 Hz), 7.94(dd, 1H, J=2.4 and 8.6 Hz), 7.31-7.18 (m, 2H), 7.06-6.98 (m, 2H), 3.41(q, 2H, J=6.7 Hz), 2.95 (t, 2H, J=7.3 Hz), 1.44 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-2-chloro-phenyl]-ethyl}-carbamicacid tert-butyl esther

The compound of step 4 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to formthe amide form nitrile have been described previously.

¹H-NMR (methanol-₄, 200 MHz): 8.62 (dd, 1H, J=0.8 and 2.7 Hz), 8.27 (dd,1H, J=2.4 and 8.6 Hz), 7.34 (d, 1H, J=8.3 Hz), 7.22 (d, 1H, J=2.4 Hz),7.07-7.02 (m, 2H), 3.34 (m, 2H), 2.92 (t, 2H, J=7.3 Hz), 1.42 (s, 9H).

Step 6 6-[4-(2-Amino-ethyl)-2-chloro-phenoxy]-nicotinamide

The compound of step 5 is subject to hydrolysis using trifluoroaceticacid. The details of the hydrolysis procedure to remove the protectinggroup have been described previously. Electrospray MS M+1 ion=292.¹H-NMR (metanol-d₄, 200 MHz): 8.60 (dd, 1H, J=0.8 and 2.7 Hz), 8.28 (dd,1H, J=2.7 and 8.9 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=2.4 Hz),7.09-7.03 (m, 2H), 2.94 (s, 4H).

Step 7

Combine compound from step 6 (60 mg, 0.21 mmol), 3-methyl-butyraldehyde(24 □l, 0.23 mmol) and 3 A molecular sieves (670 mg) in methanol (2 mL),stir the mixture at room temperature overnight. Add NaBH₄ (41 mg, 1.10mmol) and stir at room temperature for 3 hours. Filtrate the mixtureover celite and eliminate the solvent. Purify the crude mixture by SCXto obtain the title compound. Electrospray MS M+1 ion=362.

¹H-NMR (metanol-d₄, 200 MHz): 8.61 (dd, 1H, J=0.8 and 2.7 Hz), 8.27 (dd,1H, J=2.4 and 8.6 Hz), 7.38 (d, 1H, J=8.6 Hz), 7.22 (d, 1H, J=2.4 Hz),7.07-7.03 (m, 2H), 3.03-2.81 (m, 4H), 2.70-2.62 (m, 2H), 1.62 (m, 1H),1.48-1.37 (m, 2H), 0.92 (d, 6H, J=6.5 Hz).

By the method of example 9 the following examples (examples 10-14) wereprepared. The purification process is described in each case

EXAMPLE 6606-{3-Chloro-4-[2-(3,3-dimethyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=376. ¹H-NMR(metanol-d₄, 200 MHz): 8.61 (dd, 1H, J=0.5 and 2.4 Hz), 8.27 (dd, 1H,J=2.7 and 8.9 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.22 (d, 1H, J=2.4 Hz),7.09-7.03 (m, 2H), 3.02-2.81 (m, 4H), 2.69-2.61 (m, 2H), 1.49-1.40 (m,2H), 0.93 (s, 9H).

EXAMPLE 661 6-[3-Chloro-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: flash chromatography (eluent: CH₂Cl₂/MeOH 90/10).Electrospray MS M+1 ion=362. ¹H-NMR (metanol-d₄, 200 MHz): 8.61 (dd, 1H,J=0.8 and 2.4 Hz), 8.27 (dd, 1H, J=2.4 and 8.6 Hz), 7.38 (d, 1H, J=8.3Hz), 7.23 (d, 1H, J=2.4 Hz), 7.09-7.03 (m, 2H), 3.03-2.81 (m, 4H),2.68-2.61 (m, 2H), 1.61-1.47 (m, 2H), 1.37-1.28 (m, 4H), 0.93 (t, 3H,J=6.7 Hz).

EXAMPLE 6626-{3-Chloro-4-[2-(cyclohexylmethyl-amino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion =388. ¹H-NMR(metanol-d₄, 300 MHz): 8.63 (d, 1H, J=1.8 Hz), 8.28 (dd, 1H, J=2.4 and8.5 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.22 (d, 1H, J=2.2 Hz), 7.07-7.03 (m,2H), 3.01-2.81 (m, 4H), 2.49 (d, 2H, J=6.7 Hz), 1.79-1.68 (m, 5H),1.61-1.42 (m, 1H), 1.38-1.17 (m, 3H), 0.99-0.85 (m, 2H).

EXAMPLE 6636-{3-Chloro-4-[2-(3-fluoro-benzylamino)-ethyl]-phenoxy}-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion =400. ¹H-NMR(metanol-d₄, 300 MHz): 8.63 (d, 1H, J=2.2 Hz), 8.27 (dd, 1H, J=2.4 and8.7 Hz), 7.36-6.95 (m, 8H), 3.82 (s, 2H), 3.01-2.81 (m, 4H).

EXAMPLE 6646-(4-{2-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-ethyl}-3-chloro-phenoxy)-nicotinamide

Purification: SCX column. Electrospray MS M+1 ion=398. ¹H-NMR(metanol-d₄, 200 MHz): 8.61 (dd, 1H, J=0.5 and 2.4 Hz), 8.26 (dd, 1H,J=2.4 and 8.6 Hz), 7.40-7.03 (m, 4H), 6.18-5.92 (m, 2H), 3.01-2.66 (m,6H), 2.40-2.18 (m, 2H), 1.95-1.83 (m, 1H), 1.64-1.11 (m, 3H), 0.60-0.50(m, 1H).

EXAMPLE 6656-{2,6-Difluoro-4-[2-(3-methyl-butylamino)-ethyl]-phenoxy}-nicotinamide

Step 1 2,6-Difluoro-4-(2-nitro-vinyl)-phenol

Aldehyde (2,6-difluoro-4-hydroxybenzaldehyde) (2.27 g, 14.4 mmol),nitromethane (4.7 mL, 86.4 mmol) and ammonium acetate (4.4 g, 57.6 mmol)were dissolved in acetic acid (22 mL) and the reaction heated at 110° C.for 1 h 30 min. The reaction is concentrated under reduced pressure andthe residue partitioned between ether and water. Separate the layers anddry with Na₂SO₄, filter and concentrate under reduced pressure. Purifythe crude by flash chromatography (eluent: EtOAc/hexane 22/78) affordedthe title compound (2.05 g, yield: 71%). Electrospray MS M−1 ion=200.¹H-NMR (CDCl₃, 200 MHz): 7.84 (d, 1H, J=13.7 Hz), 7.45 (d, 1H, J=13.7Hz), 7.19-6.99 (m, 2H).

Step 2 4-(2-Amino-ethyl)-2,6-difluoro-phenol

To lithium aluminum hydride 1.0M in ether (30 mL, 29.8 mmol) at 0° C. asolution of aluminum trichloride (4.0 g, 29.8 mmol) in THF (40 mL) isadded. After 5 min a solution of compound obtained in step 1 above (2.0g, 9.95 mmol) in THF (40 mL) is added and the reaction is allowed tostir at room temperature overnight. Add water and then 3 N HCl, theaqueous layer is extracted with 3/1 n-butanol/toluene. The combinedorganic layers are dried over sodium sulfate and concentrated. SCXion-exchange chromatography afforded 1.50 g (87%) of the title compound.Electrospray MS M+1 ion=174. ¹H-NMR (methanol-d₄, 200 MHz): 6.95-6.78(m, 2H), 3.14 (t, 2H, J=7.0 Hz), 2.86 (t, 2H, J=7.3 Hz).

Step 3 [2-(3,5-Difluoro-4-hydroxy-phenyl)-ethyl]-carbamic acidtert-butyl ester

Dissolve amine obtained in step 2 above (1.5 g, 8.67 mmol) in dry THF(22 mL) under N₂ atmosphere, add a solution of di-tertbutyl dicarbonate(1.89 g, 8.67 mmol) in THF (22 mL), stir the mixture at room temperatureovernight. Eliminate the solven. Purify by flash chromatography (eluent:EtOAc/hexane 1/4 and 1/1) to obtain the desired compound (1.40 g).¹H-NMR (CDCl₃, 200 MHz): 6.85-6.66 (m, 2H), 3.31 (q, 2H, J=6.2 Hz), 2.69(t, 2H, J=7.0 Hz), 1.44 (s, 9H).

Step 4{2-[4-(5-Cyano-pyridin-2-yloxy)-3,5-difluoro-phenyl]-ethyl}-carbamicacid tert-butyl esther

A solution of phenol obtained in step 3 above (1.31 g, 4.8 mmol),6-chloronicotinonitrile (700 mg, 5.04 mmol) and sodium hydride (290 mg,7.2 mmol) in DMSO (25 mL) is stirred at room temperature for 18 h. Pourthe mixture into iced water and extract the aqueous layer with EtOAc.Dry the organic layer over Na₂SO₄, filtrate and eliminate the solvent.Purify by flash chromatography (EtOAc/hexane 20/80 and 34/66) to get thetitle compound (950 mg, 51%). ¹H-NMR (CDCl₃, 200 MHz): 8.41 (dd, 1H,J=0.8 and 2.1 Hz), 7.97 (dd, 1H, J=2.4 and 8.6 Hz), 7.18 (dd, 1H, J=0.8and 8.6 Hz), 6.92-6.81 (m, 2H), 3.39 (q, 2H, J=6.9 Hz), 2.81 (t, 2H,J=6.7 Hz), 1.45 (s, 9H).

Step 5{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-3,5-difluro-phenyl]-ethyl}-carbamicacid tert-butyl esther

The compound of step 4 is subject to hydrolysis using hydrogen peroxideand potassium carbonate. The details of the hydrolysis procedure to formthe amide form nitrile have been described exhaustively somewhere inP-15876.

¹H-NMR (metanol-d₄, 300 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H,J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-6.98 (m, 2H), 3.35-3.30(m, 2H), 2.81 (t, 2H, J=7.1 Hz), 1.44 (s, 9H).

Step 6 6-[4-(2-Amino-ethyl)-2,6-difluoro-phenoxy]-nicotinamide

To a solution of compound of step 5 (930 mg, 2.37 mmol) in CH₂Cl₂ (50mL), trifluoroacetic acid is added (4.7 mL, 61.5 mmol). Stir thereaction mixture at room temperature for 2 h. Eliminate the solvent andpurify by SCX column to obtain the title compound (658 mg, 95%).Electrospray MS M⁺+1 ion: 294. ¹H-NMR (metanol-d₄, 200 MHz): 8.56 (d,1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4 and 8.9 Hz), 7.18 (d, 1H, J=8.9 Hz),7.05-6.95 (m, 2H), 2.96-2.74 (m, 4H).

Step 7

Combine 3-methyl-butylaldehyde (26 μl, 0.24 mmol), amine from step 6above and 3 A molecular sieves (900 mg) in methanol (3 mL), stir themixture at room temperature overnight. Add NaBH₄ (45 mg, 1.20 mmol) andstir at room temperature for 3 hours. Filtrate the mixture over celiteand eliminate the solvent. Submit the crude to a SCX column to obtain asolid which was further purified by HPLC (Column: X-Terra MS C18. A=10Mm NH₄HCO₃ pH8/B═CH₃CN. Gradient mode: from 30 to 70% B. Flow rate: 1mL/min) to obtain the title compound (42 mg). Electrospray MS M+1ion=364. ¹H-NMR (metanol-d₄, 300 MHz): 8.60 (d, 1H, J=2.0 Hz), 8.32 (dd,1H, J=2.2 and 8.5 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.01-6.98 (m, 2H), 2.85(m, 4H), 2.63 (m, 2H), 1.62 (m, 1H), 1.42 (q, 1H, J=7.3 Hz), 0.92 (d,6H, J=6.5 Hz).

By the method of example 665 the following examples (examples 666-669)were prepared. The purification process is described in each case

EXAMPLE 6666-{4-[2-(3,3-Dimethyl-butylamino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B═CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min ). Electrospray MSM+1 ion=378. ¹H-NMR (metanol-d₄, 300 MHz): 8.48 (d, 1H, J=2.4 Hz), 8.23(dd, 1H, J=2.4 and 8.5 Hz), 7.12 (d, 1H, J=8.5 Hz), 7.00-6.93 (m, 2H),2.91-2.78 (m, 4H), 2.67-2.61 (m, 2H), 1.43-1.38 (m, 2H), 0.87 (s, 9H).

EXAMPLE 6676-[2,6-Difluoro-4-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B═CH₃CN.Gradient mode: from 25 to 70% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=364. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.32(dd, 1H, J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-7.00 (m, 2H),2.88 (m, 4H), 2.65 (t, 2H, J=7.3 Hz), 1.55 (m, 2H), 1.35 (m, 4H), 0.93(t, 3H, J=6.7 Hz).

EXAMPLE 6686-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B═CH₃CN.Gradient mode: from 30 to 99% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=390. ¹H-NMR (metanol-d₄, 300 MHz): 8.48 (d, 1H, J=2.4 Hz), 8.23(dd, 1H, J=2.4 and 8.9 Hz), 7.11 (d, 1H, J=8.8 Hz), 6.99-6.92 (m, 2H),2.83 (m, 4H), 2.47 (d, 2H, J=6.9 Hz), 1.72-1.59 (m, 5H), 1.55-1.41 (m,1H), 1.31-1.05 (m, 3H), 0.94-0.81 (m, 2H).

EXAMPLE 6696-{4-[2-(Cyclopropylmethyl-amino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

Purification: HPLC (Column: X-Terra MS C18. A=10 Mm NH₄HCO₃ pH8/B=MeOH.Gradient mode: from 35 to 80% B. Flow rate: 1 mL/min). Electrospray MSM+1 ion=348. ¹H-NMR (metanol-d₄, 300 MHz): 8.59 (d, 1H, J=2.4 Hz), 8.32(dd, 1H, J=2.4 and 8.7 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.02-7.00 (m, 2H),2.93-2.83 (m, 4H), 2.50 (d, 2H, J=6.9 Hz), 1.10-0.90 (m, 1H), 0.55-0.49(m, 2H), 0.20-0.15 (m, 2H).

GENERAL PROCEDURE: REDUCTIVE AMINATION (EXAMPLES 670-693)

To a mixture of amine (1 equiv), aldehyde (1.5 equiv) in 5%AcOH/methanol (0.2 M) was added NaCNBH₄ (5 equiv) and the resultingreaction mixture was stirred for 2 hours under nitrogen atmosphere atroom temperature. The reaction can be monitored by electrospray MS orTLC. Ethyl acetate was added to the reaction mixture and washed twicewith saturated aqueous solution of NaHCO₃. The organic layer wasseparated, dried over anhydrous NaSO₄ and the solvent evaporated toyield a residue which was purified by flash chromatography usingchloroform/ethanol/NH₄OH, 94.5/5/0.5) to afford the title compound as awhite solid.

EXAMPLE 6706-[4-((3-Methyl-butyl),cyclopropylmethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title compound was prepared by reductive amination of6-[2-fluoro-4-((3-methyl-butyl)aminomethyl)phenoxy]nicotinamide withcyclopropylcarboxaldehyde.

83% Yield. Mp 94-5° C.

¹H NMR (CHCl₃-d₃) δ: 8.55 (d, 1H, J=2.4 Hz), 8.15 (dd, 1H, J=8.5, 2.4Hz), 7.28-7.10 (m, 3H), 6.98 (d, 1H, J=8.5 Hz), 6.53 (bs, 2H), 3.62 (s,2H), 2.56 (t, 2H, J=7.4 Hz), 2.33 (d, 2H, J=7.4 Hz), 1.65-1.55 (m, 1H),1.55-1.40 (m, 2H), 0.85 (d, 6H+1H, J=6.5 Hz), 0.47 (m, 2H), 0.53 (m,2H). ¹³C NMR (CHCl₃-d₃) δ: 167.9, 165.4, 156.4, 153.1, 147.6, 139.7,139.3, 125.0, 123.5, 117.3, 110.9, 59.0, 58.0, 52.3, 36.2, 26.6, 23.1,8.9, 4.3. MS (Electrospray): 386.2 (M⁺+1).

EXAMPLE 6716-[4-((3-Methyl-butyl),cyclohexylmethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title compound was prepared by reductive amination of6-[2-fluoro-4-((3-methyl-butyl)aminomethyl)phenoxy]nicotinamide withcyclohexylcarboxaldehyde.

71% Yield. Mp 110-1° C.

¹H NMR (CDCl₃-d₃) δ: 8.55 (d, 1H, J=2.3 Hz), 8.15 (dd, 1H, J=8.6, 2.3Hz), 7.28-7.10 (m, 3H), 6.98 (d, 1H, J=8.6 Hz), 6.37 (bs, 2H), 3.49 (s,2H), 2.40 (t, 2H, J=7.2 Hz), 2.15 (d, 2H, J=7.2 Hz), 1.75-1.10 (m, 13H),1.55-1.40 (m, 2H), 0.83 (d, 6H+1H, J=6.6 Hz). ¹³C NMR (CHCl₃-d₃) δ:167.8, 165.5, 156.4, 153.1, 147.5, 139.7, 139.1, 124.9, 123.5, 117.2,110.9, 69.0, 61.8, 58.9, 52.9, 43.0, 36.5, 32.2, 29.9, 26.5, 23.0. MS(Electrospray): 428.4 (M⁺+1).

EXAMPLE 6726-[4-(((3-Pyridylethyl),ethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title compound was prepared by reductive amination of6-[2-fluoro-4-((3-methyl-butyl)aminomethyl)phenoxy]nicotinamide withacetaldehyde.

51% Yield.

¹H NMR (CHCl₃-d₃) δ: 8.58 (bs, 1H), 8.40 (bs, 2H), 8.20 (dd, 1H, J=8.9,2.4 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.25 (dd, 1H, J=7.9, 3.8 Hz), 7.15-7.00(m, 4H), 6.80 (bs, 1H), 6.20 (bs, 1H), 3.59 (s, 2H), 2.70 (m, 4H), 2.55(c, 2H, J=7.0 Hz), 1.04 (t, 3H, J=7.0 Hz). ¹³C NMR (CHCl₃-d₃) δ: 167.7,165.3, 156.4, 153.1, 150.3, 147.6, 139.8, 139.5, 139.4, 139.3, 136.8,136.4, 125.0, 124.7, 123.6, 116.9, 110.9, 57.6, 57.7, 47.7, 31.3, 12.2.MS (Electrospray): 395.4 (M⁺+1).

EXAMPLE 6736-[4-(Cyclopropylmethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with cyclopropylmethyl amine and6-(4-formyl-2-fluorophenoxy)nicotinamide.

58% Yield. MP 128-9° C.

¹H NMR (MeOH-d₄) δ: 8.60 (d, 1H, J=2.4 Hz), 8.27 (dd, 1H, J=8.7, 2.4Hz), 7.33-7.18 (m, 3H), 6.98 (d, 1H, J=8.7 Hz), 3.81 (s, 2H), 2.44 (d,1H, J=6.7 Hz), 1.00 (m, 1H), 0.51 (m, 2H), 0.16 (m, 2H). ¹³C NMR(MeOH-d₄) δ: 170.0, 166.6, 157.9, 154.6, 149.1, 141.0, 140.7, 126.8,126.3, 125.3, 118.2, 111.8, 55.2, 53.7, 11.8, 4.5. MS (Electrospray):316.1 (M⁺+1).

EXAMPLE 6746-[4-(Cyclohexylmethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with cyclohexylmethyl amine and6-(4-formyl-2-fluorophenoxy)nicotinamide.

58% Yield. MP 152-3° C.

¹H NMR (MeOH-d₄) δ: 8.60 (d, 1H, J=2.2 Hz), 8.26 (dd, 1H, J=8.5, 2.2Hz), 7.35-7.15 (m, 3H), 7.01 (d, 1H, J=8.7 Hz), 3.78 (s, 2H), 2.45 (d,1H, J=6.7 Hz), 1.90-1.65 (m, 5H), 1.55 (m, 1H), 1.45-1.15 (m, 3H),1.00-0.80 (m, 2H). ¹³C NMR (MeOH-d₄) δ: 170.0, 166.7, 157.9, 154.6,149.1, 141.2, 140.8, 126.8, 126.3, 125.3, 118.2, 111.7, 57.0, 54.1,39.2, 32.9, 28.1, 27.5. MS (Electrospray): 358.1 (M⁺+1).

EXAMPLE 675 6-[4-(Cycloheptylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with cycloheptylamine and6-(4-formyl-2-fluorophenoxy)nicotinamide.

69% Yield.

¹H NMR (MeOH-d₄) δ: 8.59 (d, 1H, J=2.2 Hz), 8.26 (dd, 1H, J=8.5, 2.2Hz), 7.34-7.18 (m, 3H), 7.10 (d, 1H, J=8.7 Hz), 3.80 (s, 2H), 2.75 (bs,1H), 1.85-1.70 (m, 5H), 1.70-1.35 (m, 7H). ¹³C NMR (MeOH-d₄) δ: 170.0,166.7, 157.9, 154.6, 149.1, 141.2, 126.8, 126.4, 126.3, 125.3, 118.3,111.7, 58.3, 34.9, 28.6, 27.4, 25.8. MS (Electrospray): 358.1 (M⁺+1).

EXAMPLE 676 6-[4-(Cyclooctylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with cyclooctylamine and6-(4-formyl-2-fluorophenoxy)nicotinamide in 49% Yield.

¹H NMR (MeOH-d₄) δ: 8.59 (d, 1H, J=2.4 Hz), 8.26 (dd, 1H, J=8.7, 2,4Hz), 7.40-7.20 (m, 3H), 7.08 (d, 1H, J=8.7 Hz), 3.78 (s, 2H), 2.68 (bs,1H), 2.00-1.85 (m, 2H), 1.80-1.40 (m, 14H). ¹³C NMR (MeOH-d₄) δ: 170.0,166.7, 157.9, 154.6, 149.1, 141.1, 140.9, 126.8, 126.3, 125.3, 118.2,111.7, 59.6, 51.4, 38.8, 35.6, 29.7, 26.0. MS (Electrospray): 372.3(M⁺+1).

EXAMPLE 677 6-[4-(tert-butylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with tert-butylamine and6-(4-formyl-2-fluorophenoxy)nicotinamide in 12% yield.

¹H NMR (MeOH-d₄) δ: 8.58 (d, 1H, J=2.4 Hz), 8.27 (dd, 1H, J=8.7, 2.4Hz), 7.35-7.20 (m, 3H), 7.10 (d, 1H, J=8.7 Hz), 3.75 (s, 2H), 1.22 (s,9H). ¹³C NMR (MeOH-d₄) δ: 170.1, 166.7, 157.6, 154.6, 149.0, 141.6,141.5, 126.8, 126.4, 125.3, 118.4, 111.6, 52.4, 47.5, 29.1. MS(Electrospray): 318.1 (M⁺+1).

EXAMPLE 6786-[4-(2-furylmethylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title product was prepared following standard reductive aminationtechniques with 2-furylmethylamine and6-(4-formyl-2-fluorophenoxy)nicotinamide.

27% Yield.

¹H NMR (MeOH-d₄) δ: 8.60 (d, 1H, J=2.0 Hz), 8.26 (dd, 1H, J=8.7, 2.0Hz), 7.46 (bs, 1H), 7.30-7.15 (m, 3H), 7.08 (d, 1H, J=8.5 Hz), 6.37 (bs,1H), 6.29 (bs, 1H), 3.77 (s, 4H). ¹³C NMR (MeOH-d₄) δ: 170.0, 166.7,158.0, 154.8, 149.1, 143.7, 141.2, 140.5, 140.4, 126.8, 126.4, 126.3,125.3, 118.3, 111.7, 109.1, 52.9, 46.0. MS (Electrospray): 342.1 (M⁺+1).

EXAMPLE 679(S)-6-[4-(Methylbenzylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title compound prepared following standard reductive amination with(S)-methylbenzylamine and 6-(4-formyl-2-fluorophenoxy)nicotinamide.

50% Yield.

¹H NMR (MeOH-d₄) δ: 8.59 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=8.5, 2.0Hz), 7.40-7.30 (m, 4H), 7.28 (m, 1H), 7.18 (m, 2H), 7.09 (m, 2H), 3.81(c, 1H, J=6.7 Hz), 3.60 (AB system, 2H), 1.39 (d, 3H, J=6.7 Hz). ¹³C NMR(MeOH-d₄) δ: 170.1, 166.7, 157.9, 154.6, 149.0, 146.4, 141.2, 130.0,128.4, 127.2, 126.8, 126.3, 126.2, 125.2, 118.1, 111.7, 58.9, 51.7,24.5. MS (Electrospray): 366.1 (M⁺+1).

EXAMPLE 680(R)-6-[4-(Methylbenzylaminomethyl)-2-fluorophenoxy]nicotinonamide

The title compound was prepared following standard reductive aminationwith (R)-methylbenzylamine and 6-(4-formyl-2-fluorophenoxy)nicotinamide.

39% Yield.

¹H NMR (MeOH-d₄) δ: 8.59 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=8.5, 2.0Hz), 7.40-7.30 (m, 4H), 7.28 (m, 1H), 7.18 (m, 2H), 7.09 (m, 2H), 3.81(c, 1H, J=6.7 Hz), 3.60 (AB system, 2H), 1.39 (d, 3H, J=6.7 Hz). ¹³C NMR(MeOH-d₄) δ: 170.1, 166.7, 157.9, 154.6, 149.0, 146.4, 141.2, 130.0,128.4, 127.2, 126.8, 126.3, 126.2, 125.2, 118.1, 111.7, 58.9, 51.7,24.5. MS (Electrospray): 366.1 (M⁺+1).

EXAMPLE 681 Synthesis of6-(4-Ethylaminomethyl-2-fluoro-phenoxy)-nicotinamide

Using ethylamine and 2-fluoro-4-formylphenoxynicotinamide, the titleproduct was obtained in 72% Yield

¹H NMR (DMSO, 300 MHz) δ: 8.54 (dd, J=1.8, 1H), 8.27 (dd, J=7.4, 1.6 Hz,1H), 8.00 (br s, 1H), 7.46 (br s, 1H), 7.3-7.1 (m, 4H), 3.68 (s, 2H),2.49 (q, 2H), 1.02 (t, J=4.6 Hz, 3H). MS (Electrospray): (M⁺+1) 290.2

EXAMPLE 682 Synthesis of6-(2-Fluoro-4-propylaminomethyl-phenoxy)-nicotinamide

Using n-propylamine and 2-fluoro-4-formylphenoxynicotinamide, the titleproduct was obtained.

MS (Electrospray): (M⁺+1) 304.2 (M⁺−1) 302.3 HPLC=90% @ 5.66 m (5/95 to95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15cm×5 micron, λ=254 nM.de

EXAMPLE 683 Synthesis of6-(2-Fluoro-4-hexylaminomethyl-phenoxy)-nicotinamide

Using hexylamine and 2-fluoro-4-formylphenoxynicotinamide, the titleproduct was obtained.

MS (Electrospray): (M⁺+1) 346.2 (M⁺−1) 344.4 HPLC=98% @ 5.98 m (5/95 to95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15cm×5 micron, λ=254 nM.de

EXAMPLE 684 Synthesis of6-[2-Fluoro-4-(isobutylamino-methyl)-phenoxy]-nicotinamide

Using isopropylamine and 2-fluoro-4-formylphenoxynicotinamide, the titleproduct was obtained.

MS (Electrospray): (M⁺+1) 318.2 HPLC=94% @ 5.72 m (5/95 to 95/5ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5micron, λ=254 nM.de

EXAMPLE 685 Synthesis of6-[2-Fluoro-4-(isobutylamino-methyl)-phenoxy]-nicotinamide

Using 2,2-dimethylpropyl amine and 2-fluoro-4-formylphenoxynicotinamide,the title product was obtained.

MS (Electrospray): (M⁺+1) 332.2 (M⁺−1) 330.4 HPLC=99% @ 5.79 m (5/95 to95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15cm×5 micron, λ=254 nM.de

EXAMPLE 686 Synthesis of3-Fluoro-4-{4-[(2-pyridin-2-yl-ethylamino)-methyl]-phenoxy}-benzamide

Using 2-pyridino-2-ethylamine and 4-formylphenoxy-3-fluorobenzamide(Example 243, step 3), the title product was obtained in 52% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 8.41 (d, J=1.8, 1H), 8.37 (dd, J=4.8, 1.5 Hz,1H), 7.78 (d, J=1.8, 1H), 7.74-7.64 (m, 2H), 7.38-7.33 (m, 3H),7.07-6.97 (m, 3H), 3.77 (s, 2H), 2.85 (s, 4H). HPLC=94% @ 5.56 m (5/95to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6mm×15 cm×5 micron, λ=254 nM.de MS (Electrospray): (M⁺+1) 366.1 (M⁺−1)364.3

EXAMPLE 687 Synthesis of2-Fluoro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Using 3-methylbutylamine and 4-formylphenoxy-2-fluorobenzamide, thetitle product was obtained in 10% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 7.82 (m, 1H), 7.42 (d, J=8.7Hz, 2H), 7.07 (d,J=8.7 Hz, 2H), 6.83 (dd, J=6.9, 2.1 Hz, 1H), 6.72 (dd, J=12.6, 2.1 Hz,1H), 3.77 (s, 2H), 2.65-2.59 (m, 2H), 1.66-1.57 (m, 1H), 1.47-1.40 (m,2H), 0.91 (d, J=6.6 Hz, 6H). MS (Electrospray): (M⁺+1) 331.2

EXAMPLE 688 Synthesis of3-Methoxy-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Using 3-methylbutylamine and 4-formylphenoxy-3-methoxybenzamide, thetitle product was obtained in 15% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 7.62 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.1, 1.8Hz, 1H), 7.30 (d, J=8.7, 2H), 6.96 (d, J=8.1, 1H), 6.88 (d, J=8.4, 2H),3.77 (s, 2H), 2.62-2.57 (m, 2H), 1.65-1.56 (m, 1H), 1.46-1.38 (m, 2H),0.90 (d, J=6.6 Hz, 6H). MS (Electrospray): (M⁺+1) 343.25 HPLC=98% @ 5.95m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.de

EXAMPLE 689 Synthesis of2-Methyl-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Using 3-methylbutylamine and 4-formylphenoxy-2-methylbenzamide, thetitle product was obtained in 71% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 7.42 (d, J=8.4 Hz, 1H), 7.36 (d, J=6.6 Hz,2H), 6.97 (d, J=8.4, 2H), 6.67-6.83 (m, 2H), 3.74 (s, 2H), 2.65-2.58 (m,2H), 2.40 (s, 3H), 1.63-1.59 (m, 1H), 1.47-1.39 (m, 2H), 0.91 (d, J=6.6Hz, 6H). MS (Electrospray): (M⁺+1) 341.3 (M⁺−1) 239.4 HPLC=91% @ 6.07 m(5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl4.6 mm×15 cm×5 micron, λ=254 nM.de

EXAMPLE 690 Synthesis of3-Methyl-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Using 3-methylbutylamine and 4-formylphenoxy-3-methylbenzamide, thetitle product was obtained in 60% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 7.81 (d, J=0.9 Hz, 1H), 7.68-7.64 (m 1H),7.35 (d, J=6.6, 2H), 6.92 (d, J=6.6, 2H), 6.81 (d, J=6.6, 1H), 3.75 (s,2H), 2.64-2.60 (m, 2H), 2.31 (s, 3H), 1.64-1.60 (m, 1H), 1.47-1.41 (m,2H), 0.92 (d, J=6.6 Hz, 6H). MS (Electrospray): (M⁺+1) 327.2

EXAMPLE 691 3-Fluoro-4-{4-[3-methylbutylamino)-methyl]phenoxy}-benzamide

Reductive amination using the intermediate of Example 243 step 3, and 3and 3-methylbutylamine, afforded the title compound in 96% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 7.76 (dd, J=11.6, 2.2 Hz, 1H), 7.69-7.63 (m,1H), 7.36 (d, J=6.7 Hz, 2H), 7.08-6.97 (m, 3H), 3.73 (s, 2H), 2.65-2.55(m, 2H), 1.67-1.53 (m, 1H), 1.47-1.36 (m, 2H), 0.90 (d, J=6.4 Hz, 6H).HPLC=98% @ 6.00 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes,Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.de MS (APCI): (M⁺+1)331.1

EXAMPLE 6923-Fluoro-4-{4-[(3,3-Dimethyl-butylamino)-methyl]-phenoxy}-3-fluoro-benzamide

Reductive amination using the intermediate of Example 243 step 3, and3,3-dimethylbutylamine, afforded the title compound in 62% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 7.76 (dd, J=11.6, 2.2 Hz, 1H), 7.74-7.64 (m,1H), 7.36 (d, J=6.7 Hz, 2H), 7.08-6.97 (m, 3H), 3.73 (s, 2H), 2.64-2.56(m, 2H), 1.49-1.41 (m, 2H), 2.1 (s, 9H). MS (APCI): (M⁺+1) 345.2

EXAMPLE 693 3-Fluoro-4-(4-pentylaminomethyl-phenoxy)-benzamide

Reductive amination using the intermediate of Example 243 step 3, andpentylamine, afforded the title compound in 94% Yield.

¹H NMR (CD₃OD, 200 MHz) δ: 7.77 (dd, J=11.6, 2.2 Hz, 1H), 7.74-7.69 (m,1H), 7.36 (d, J=6.7 Hz, 2H), 7.08-6.97 (m, 3H), 3.73 (s, 2H), 2.60-2.53(m, 2H), 1.57-1.50 (m, 2H), 1.39-1.29 (m, 4H), 0.91 (t, J=6.7 Hz, 3H).MS (APCI): (M⁺+1) 331.1

EXAMPLE 6943,5-Difluoro-4-{4-[3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Step 1 3,5-Difluoro-4-(4-formyl-phenoxy)benzonitrile

Basic displacement reaction of 4-hydroxy benzaldehyde and3,5-difluorobenzonitrile using potassium carbonate in anhydrous DMF atreflux temperatures affords the above compound.

76% Yield

¹H NMR (CDCl₃, 200 MHz) δ: 9.93 (s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.38(d, J=6.6 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃, 300 MHz) δ:189.9, 157.4, 152.0 (d, ¹J_(CF)=252.1), 146.9 (d, ²J_(CF)=11.0), 132.2,132.0, 129.0, 128.7, 128.6, 120.3, 120.0, 119.9 (d, ³J_(CF)=1.4), 116.7,116.3 (d, ³J_(CF)=2.3), 107.1 (d, ²J_(CF)=8.1), 15.0.

Step 2 3,5-Difluoro-4-(4-formyl-phenoxy)benzamide

Hydrolysis of the compound of step 1 using hydrogen peroxide andpotassium carbonate in DMSO as described previously afford the abovecompound in 99% yield.

¹H NMR (DMSO, 200 MHz) δ: 9.89 (s, 1H), 8.15 (brs, 1H), 7.90 (d, J=8.8Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.71 (brs, 1H), 7.18 (d, J=8.8 Hz, 2H).MS (APCI): (M⁺+1) 278.0 (M⁺−1) 276.0

Step 33,5-Difluoro-4-{4-[3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Reductive amination of the compound of step 2 with 3-methylbutylamineaffords the title compound in 61% Yield

¹H NMR (CD₃OD, 200 MHz) δ: 7.66 (d, J=8.9 Hz, 2H), 7.31 (d, J=8.6 Hz,2H), 6.91 (d, J=8.6 Hz, 2H), 3.70 (s, 2H), 2.60-2.53 (m, 2H), 1.66-1.49(m, 1H), 1.46-1.35 (m, 2H), 0.89 (d, J=6.4 Hz, 6H). MS (APCI): (M⁺+1)349.1

EXAMPLE 695 Synthesis of3-Fluoro-4-(4-{[methyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-benzamide

Reductive amination using formaldehyde and the compound of Example 691affords the title product.

¹H NMR (CD₃OD, 300 MHz) δ: 7.76 (dd, J=11.4, 1.8 Hz, 1H), 7.68-7.65 (m,1H), 7.34 (d, J=6.6, 2H), 7.08 (m, 1H), 7.00 (d, J=6.6, 2H), 3.51 (s,2H), 2.44-2.39 (m, 2H), 2.20 (s, 3H), 1.60-1.55 (m, 1H), 1.47-1.39 (m,2H), 0.90 (d, J=6.6 Hz, 6H). MS (Electrospray): (M⁺+1) 345.2 (M⁺−1)343.3

EXAMPLE 696 Synthesis of3,5-Difluoro-4-(4-{[methyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-benzamide

Reductive amination using formaldehyde and the compound of Example 694,step 3 affords title product in 66% Yield.

¹H NMR (CD₃OD, 300 MHz) δ: 7.66 (d, J=9.0 Hz, 2H), 7.28 (d, J=8.4 Hz,2H), 6.90 (d, J=8.4 Hz, 2H), 3.47 (s, 2H), 2.41-2.36 (m, 2H), 2.17 (s,3H), 1.60-1.50 (m, 1H), 1.45-1.39 (m, 2H), 0.88 (d, J=6.6 Hz, 6H). MS(Electrospray): (M⁺+1) 363.2 (M⁺−1) 361.3

EXAMPLE 697

Synthesis of

To a solution of Example 227 in chloroform was added m-CPBA (1.01 equiv)and the reaction mixture stirred for 6 hours at room temperature. It wasquenched with few drops of sodium bicarbonate. The organic phase wasseparated and dried over magnesium sulphate, filtered and concentratedto yield a white solid. Purify by eluting through a 5 g ISCO® columnCHCl₃: 30% (EtOH:NH₄OH 10%) to afford the title compound as a solid.

20% Yield

¹H NMR (CD₃OD, 300 MHz) δ: 8.59 (dd, J=1.8, 0.9 Hz, 1H), 8.28-8.25 (m,1H), 7.55 (s, 1H), 7.46 (d, J=8.4, Hz 1H), 7.11 (d, J=8.1 Hz, 1H), 7.03(d, J=8.7 Hz, 1H), 4.37 (q, 2H), 3.12-3.07 (m, 2H), 2.99 (s, 3H), 2.17(s, 3H), 2.00-1.80 (m, 1H), 1.81-1.70 (m, 1H), 1.69-1.60 (m, 1H), 0.98(dd, J=6.6, 1.2 Hz, 6H). MS (Electrospray): (M⁺+1) 358.1 (M⁺−1) 356.3HPLC=90% @ 5.94 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes,Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.de

EXAMPLE 6984-{2-Chloro-4-[(2-thiophen-2-yl-ethylamino)-methyl]-phenoxy}-benzamide

Step 1: Preparation of Intermediate 14-(2-Chloro-4-formyl-phenoxy)-benzamide

Mix 3-chloro-4-fluorobenzaldehyde (3.28 g, 20.7 mmol),4-hydroxybenzamide (3.12 g, 22.7 mmol), potassium carbonate (4.29 g,31.0 mmol) and dimethylacetamide (80 mL) in a flask. Heat the reactionto 100° C. for 3 hours. Let cool to ambient (room) temperature and pourinto water (200 mL). After trituration, filter the solid formed and dryon a vacuum pump to obtain the product (5.35 g, 94%). ¹H NMR (DMSO-d₆)9.94 (s, 1H), 8.13 (d, J=1.7 Hz, 1H), 7.98 (bs, 1H), 7.94 (d, J=8.5 Hz,2H), 7.88 (dd, J=1.7 Hz, 8.5 Hz, 1H), 7.36 (bs, 1H), 7.21 (d, J=8.5 Hz,1H), 7.14 (d, J=8.5 Hz, 2H).

Step 2:

Mix 4-(2-chloro-4-formyl-phenoxy)-benzamide (0.19 g, 0.70 mmol),2-thiophen-2-yl-ethylamine (0.074 mL, 0.63 mmol), and methanol (8 mL) ina 20 mL vial. After the reaction mixture solubilizes, add 3 Å molecularsieves (0.50 g) and stir for 8 hrs. Cool in an ice bath for 10 min andadd sodium borohydride (0.048 g, 1.27 mmol). Remove ice bath and stirfor 2 hrs. Purify by placing directly onto an SCX column (5 g) usingmethanol to load and wash and 2M NH₃ in CH₃OH as eluant to obtain theproduct (0.23 g, 94%), Serial number 2136018. Mass spectrum (ion spray):m/z=387.2 (M+1); ¹H NMR (DMSO-d₆) 7.89 (bs, 1H), 7.86 (d, J=8.5 Hz, 2H),7.57 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.30-7.26 (m, 2H), 7.16 (d, J=8.8Hz, 1H), 6.95-6.84 (m, 4H), 3.74 (s, 2H), 2.94 (t, J=7.1 Hz, 2H), 2.75(t, J=7.1 Hz, 2H).

EXAMPLE 6994-{2-Chloro-4-[(3,3-dimethyl-butylamino)-methyl]-phenoxy}-benzamide

Reductive amination of the compound of Example 698, Step 1 and3,3,dimethylbutylamine affords the title product (0.21 g, 99%). Massspectrum (ion spray): m/z=361.3 (M+1); ¹H NMR (DMSO-d₆) 7.89 (bs, 1H),7.86 (d, J=7.7 Hz, 2H), 7.56 (s, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.28 (bs,1H), 7.16 (d, J=7.7 Hz 1H), 6.89 (d, J=7.7 Hz, 2H), 3.69 (s, 2H), 2.49(t, J=7.7 Hz, 2H), 1.35 (t, J=7.7 Hz, 2H), 0.85 (s, 9H).

EXAMPLE 7004-{2-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Reductive amination of the compound of Example 698, Step 1 and3-methylbutylamine affords the title product (0.20 g, 92%). Massspectrum (ion spray): m/z=347.3 (M+1);

¹H NMR (DMSO-d₆) 7.90 (bs, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.55 (s, 1H),7.33 (d, J=8.3 Hz, 1H), 7.28 (bs, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.89 (d,J=8.3 Hz, 2H), 3.67 (d, J=6.7 Hz, 2H), 2.46 (t, J=7.8 Hz, 2H), 1.61(septet, J=6.7 Hz, 1H), 1.30 (q, J=6.7 Hz, 2H), 0.83 (d, J=6.7 Hz, 6H).

EXAMPLE 701

Step 1

4-Hydroxybenzaldehyde (2.94 mol), 2-chloro-5-cyanopyridine (2.94 mol)and approximately 5.7 L of dimethylacetamide were stirred under nitrogenatmosphere. Potassium carbonate (6.17 mol) was added and the mixture washeated the at about 100° C. for about 4 hours or until complete asdetermined by HPLC analysis The mixture was The reaction mixture wasstirred overnight at room temperature. The product was precipitated byadding ice water and allowing to cool with stirring. The product wasfiltered and the wetcake was rinsed with water. After air drying, theproduct was further dried under vacuum at 50° C.

Step 2

The product of step 1 (2.86 mol), potassium carbonate (1.42 mol), andDMSO (2.6 L) were stirred at room temperature. The mixture was thencooled to 18° C. in an ice-bath, followed by the dropwise addition of30% hydrogen peroxide (321 mL, 3.14 mol). The observed exotherm wascontrolled to 52° C. by a slow peroxide addition rate and adding moreice to the ice-bath. The progress of the reaction was monitored by HPLCwhich showed consumption of the nitrile. The mixture was allowed to warmto room temperature, poured into ice water (about 13 L) and stirred for45 minutes. The mixture was vacuum filtered and rinsed with water (2×3L). The solid was further dried in a vacuum oven at 50° C. for 3 days toafford approximately 80% yield.

Step 3:

The product of step 2 (2.28 mmol), 672 grams of activated molecularsieves, and isopentylamine (3.42 mol) were stirred in methanol (12.5 L)at room temperature. The mixture was stirred overnight (approximately 16hours) at room temperature. Upon consumption of the aldehyde asdetermined by HPLC analysis, sodium borohydride (34.50 g) was added as asolid in 25 gram portions until used up. The reaction mixture wasstirred overnight at room temperature and worked as described previously(adjusting for larger amounts of compound) following proceduresdescribed previously. To afford about a 93% step 3 yield.

Step 4

The product of step 3 (1.66 mol) was dissolved in 95:5 EtOH/H₂Osolvents. The solution was heated to 60° C. followed by addition 1N HClsolution (1.66 L) over 15 minutes at 60° C. An additional 500 mL of 95:5ethanol/water was added to rinse in all of the HCl solution. Theresulting mixture was stirred at 60° C. for 2 hours. The mixture wasallowed to cool to room temperature. The mixture was filtered and thesolid was rinsed with 4×500 mL 95:5 ethanol/water. The solid was driedin a vacuum overnight at 45° C. until drying loss was negligible. Step 4yield was about 93% .

Mass spectrum (ion spray): m/z=314.7 (M+1), ¹H NMR δ (ppm) 1.03 (d, 6H),1.78 (s, 3H), 3.40 (s, 2H), 4.54 (s, 2H), 7.41-7.50 (m, 5H), 7.82-7.85(m, 2H), 9.06-9.08 (m, 1H), 9.23-9.25 (m, 1H). ¹³C NMR: δ (ppm) 20.56,25.78, 34.71, 48.06, 51.67, 112.88, 121.58, 125.66, 130.98, 133.30,140.45, 148.98, 152.17, 161.58, 166.30.

EXAMPLE 702 4-(2-Chloro-4-pentylaminomethyl-phenoxy)-benzamide

Reductive amination of the compound of Example 698, Step 1 andpentylamine affords the title product t (0.22 g, 98%). Mass spectrum(ion spray): m/z=347.3 (M+1); ¹H NMR (DMSO-d₆) 7.89 (bs, 1H), 7.86 (d,J=8.9 Hz, 2H), 7.55 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.27 (bs, 1H), 7.15(d, J=8.4 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H), 3.67 (s, 2H), 2,45 (t, J=6.7Hz, 2H), 1.45-1.37 (m, 2H), 1.28-1.23 (m, 4H), 0.87-0.82 (m, 3H).

EXAMPLE 7033-Chloro-4-{4-[(2-thiophen-2-yl-ethylamino)-methyl]-phenoxy}-benzamide

Step 1: 3-Chloro-4-(4-formyl-phenoxy)-benzonitrile

Mix 4-hydroxy-benzaldehyde (0.86 g, 7.07 mmol),3-chloro-4-fluoro-benzonitrile (1.00 g, 6.43 mmol), cesium carbonate(3.14 g, 9.64 mmol) and dimethylacetamide (30 mL) in a flask. Heat to100° C. for 4 hrs. Let cool to room temperature (rt) and pour into water(200 mL). After trituration, filter the solid formed and dry on a vacuumpump to obtain the product (1.57 g, 95%). ¹H NMR (DMSO-d₆) 9.96 (s, 1H),8.29 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.89 (dd, J=1.8 Hz, 8.6Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H).

Step 2: 3-Chloro-4-(4-formyl-phenoxy)-benzamide

Cool a solution of 3-chloro-4-(4-formyl-phenoxy)-benzonitrile (1.57 g,6.10 mmol) in dimethylsulfoxide (50 mL) to 0° C. Add potassium carbonate(0.42 g, 3.05 mmol) followed by 30% aqueous hydrogen peroxide (1.83 mL,6.10 mmol). Remove the cooling bath and let stir at rt for 3 hrs. Pourinto water (100 mL) and after trituration, filter the solid formed toobtain the product (1.40 g, 84%). ¹H NMR (DMSO-d₆) 9.93 (s, 1H), 8.12(d, J=1.2 Hz, 1H), 8.10 (bs, 1H), 7.95-7.90 (m, 3H), 7.53 (bs, 1H), 7.34(d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H).

Step 3:

Use 3-chloro-4-(4-formyl-phenoxy)-benzamide (0.20 g, 0.71 mmol),2-thiophen-2-yl-ethylamine (0.075 mL, 0.64 mmol), sodium borohydride(0.049 g, 1.29 mmol) and methanol (8 mL) in a procedure and purificationsimilar to that of Example 1, to obtain the product (0.24 g, 94%),2137632. Mass spectrum (ion spray): m/z=387.1 (M+1); ¹H NMR (CDCl₃) 7.93(d, J=2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.31 (d, J=8.5 Hz,2H), 7.14 (d, J=5.2 Hz, 1H), 6.97 (d, J=8.3 Hz, 2H), 6.93 (dd, J=3.4 Hz,5.1 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.1 Hz, 1H), 6.11 (bs,2H), 3.81 (s, 2H), 3.05 (t, J=6.7 Hz, 2H), 2.95 (t, J=6.7 Hz, 2H).

EXAMPLE 7043-Chloro-4-{4-[(3,3-dimethyl-butylamino)-methyl]-phenoxy}-benzamide

Reductive amination of the compound of Example 703, Step 2 and3,3,dimethylbutylamine affords the title product (0.21 g, 98%). Massspectrum (ion spray): m/z=361.2 (M+1); ¹H NMR (CDCl₃) 7.93 (s, 1H), 7.61(d, J=7.9 Hz, 1H), 7.33 (d, J=7.5 Hz, 2H), 6.97 (d, J=7.5 Hz, 2H), 6.87(d, J=8.3 Hz, 1H), 6.24 (bs, 2H), 3.78 (s, 2H), 2.65 (t, J=6.5 Hz, 2H),1.43 (t, J=6.5 Hz, 2H), 0.89 (s, 9H).

EXAMPLE 7053-Chloro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

Preparation using a method similar to Example 703 yields the product(0.21 g, 93. Mass spectrum (ion spray): m/z=347.2 (M+1); ¹H NMR (CDCl₃)7.93 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 6.95 (d,J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 6.49 (bs, 2H), 3.76 (s, 2H), 2.63(t, J=7.3 Hz, 2H), 1.61 (septet, J=6.5 Hz, 1H), 1.39 (q, J=7.3 Hz, 2H),0.87 (d, J=6.8 Hz, 6H).

EXAMPLE 7064-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-trifluoromethyl-phenoxy}-benzamidehydrocloride

Step 1 4-(4-Formyl-2-trifluoromethyl-phenoxy)-benzamide

Preparation using a method similar to Example 703, step 2 yields theproduct (2.00 g, 88%). ¹H NMR (DMSO-d₆) 10.02 (s, 1H), 8.33 (s, 1H),8.14 (d, J=8.6 Hz, 1H), 8.00 (bs, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.39 (bs,1H), 7.22 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 1H).

Step 2

Preparation using a method similar to Example 697 yields the product(0.17 g, 83%). Mass spectrum (ion spray): m/z=395.2 (M+1); ¹H NMR(CDCl₃) 7.79 (d, J=8.2 Hz, 2H), 7.66 (s, 1H), 7.48 (d, J=8.4 Hz, 1H),7.00-6.94 (m, 3H), 6.33 (bs, 2H), 3.81 (s, 2H), 2.65 (t, J=8.2 Hz, 2H),1.43 (t, J=8.2 Hz, 2H), 0.89 (s, 9H).

EXAMPLE 707 3-Chloro-4-(3-methoxy-4-pentylaminomethyl-phenoxy)-benzamidehydrochloride

Step 1: 3-Chloro-4-(4-formyl-3-methoxy-phenoxy)-benzonitrile

Preparation using a method similar to Example 703, step 1 yields theproduct (1.83 g, 94%). ¹H NMR (DMSO-d₆) 10.24 (s, 1H), 8.26 (s, 1H),7.87 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 3.88 (s, 3H).

Step 2: 3-Chloro-4-(4-formyl-3-methoxy-phenoxy)-benzamide

Preparation using a method similar to Example 703, step 2 yields theproduct (1.73 g, 89%). ¹H NMR (DMSO-d₆) 10.22 (s, 1H), 8.11 (d, J=1.9Hz, 1H), 8.1 (bs, 1H), 7.90 (dd, J=1.9 Hz, 8.5 Hz, 1H), 7.70 (d, J=8.7Hz, 1H), 7.54 (bs, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H),6.49 (dd, J=2.0 Hz, 8.7 Hz, 1H), 3.88 (s, 3H).

Step 3

Reductive amination of the compound of step 2 with n-pentlyamine affordsthe title product (0.18 g, 86%). Mass spectrum (ion spray): m/z=377.2(M+1); ¹H NMR (CDCl₃) 7.93 (d, J=2.0 Hz, 1H), 7.61 (dd, J=2.1 Hz, 8.7Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.59 (d, J=2.1Hz, 1H), 6.51 (dd, J=2.1 Hz, 8.2 Hz, 1H), 6.33 (bs, 1H), 6.17 (bs, 1H),3.78 (s, 3H), 3.74 (s, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.54-1.46 (m, 2H),1.33-1.25 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).

EXAMPLE 7083-Bromo-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide)

Step 1 3-Bromo-4-hydroxy-benzamide

3-Bromo-4-hydroxy-benzonitrile (495 mg, 2.5 mmol) is dissolved in H₂SO₄98%, heat the solution at 80° C. for 1 hour. Cool the mixture at roomtemperature and pour it into ice-water. Extract the aqueous layer withEtOAc. Dry the organic layer over Na₂SO₄. Eliminate the solvent toobtain the title compound (450 mg, 83%). ¹H-NMR (metanol-d₄, 200 MHz):8.04 (d, 1H, J=2.0 Hz), 7.70 (dd, 1H, J=2.0 and 8.4 Hz), 6.93 (d, 1H,J=8.6 Hz)

Step 2 3-Bromo-4-(4-formyl-phenoxy)-benzamide

Add K₂CO₃ (1.49 g, 10.8 mmol) to a solution of 4-fluorobenzaldehyde(1.16 mL, 10.8 mmol) and 3-bromo-4-hydroxy-benzamide (1.16 g, 5.4 mmol)in DMF (20 mL). Heat the mixture under N₂ overnight. Cool the mixture atroom temperature and pour it into ice-water. Extract the aqueous layerwith EtOAc. Dry the organic layer over Na₂SO₄. Eliminate the solvent.Purify by flash chromatography (eluent: EtOAc/hexane 2/1 and 4/1) to getthe title compound (1.0 g, 58%). ¹H-NMR (metanol-d₄, 300 MHz): 9.84 (s,1H), 8.18 (d, 1H, J=2.0 Hz), 7.88-7.83 (m, 3H), 7.13 (d, 1H, J=8.5 Hz),7.04-7.01 (m, 2H).

Step 3

Reductive amination using the aldehyde obtained in the previous stepfollowing general procedures described previously afforded the desiredcompound.

Electrospray MS M+1 ion=391. ¹H-NMR (metanol-d₄, 300 MHz): 8.13 (d, 1H,J=2.4 Hz), 7.73 (dd, 1H, J=2.0 and 8.5 Hz), 7.33-7.31 (m, 2H), 6.93-6.90(m, 2H), 6.83 (d, 1H, J=8.5 Hz), 3.69 (s, 2H), 2.57-2.51 (m, 2H),1.61-1.30 (m, 3H), 0.83 (d, 6H, J=6.4 Hz).

EXAMPLE 709 3-Bromo-4-(3-pentylaminomethyl-phenoxy}-benzamide

Using n-pentylbromide and following procedures similar to that ofExample 707 afforded the title compound.

Electrospray MS M+1 ion=391. ¹H-NMR (metanol-d₄, 300 MHz): 8.12 (d, 1H,J=2.0 Hz), 7.73 (dd, 1H, J=2.0 and 8.5 Hz), 7.33-7.30 (m, 2H), 6.93-6.90(m, 2H), 6.83 (d, 1H, J=8.5 Hz), 3.69 (s, 2H), 2.54-2.49 (m, 2H),1.52-1.23 (m, 6H), 0.84 (t, 3H, J=6.4 Hz).

EXAMPLE 710 6-(2,3-Difluoro-4-pentylaminomethyl-phenoxy)-nicotinamide

Step 1

2,3-Difluoro-4-hydroxy-benzaldehyde

Combine 2,3-difluoro-4-methoxy-benzaldehyde (2.76 g, 16.0 mmol) andpyridine hydrochloride (18.5 g, 160 mmol) in a round bottom flaskequipped with nitrogen inlet. Heat the mixture at 170° C. two hours,cool to near ambient temperature and dilute with water. Extract aqueouswith EtOAc (2×), wash extract with 0.1 N aq. HCl (2×), water (2×) andbrine, dry (MgSO₄) and concentrate. Purify on silica gel (20%EtOAc/Hexane) to give 2,3-difluoro-4-hydroxy-benzaldehyde (1.71 g) as ayellow solid. ¹HNMR (CDCl₃): 10.18 (s, 1H), 7.59 (t, 1H), 6.90 (t, 1H),6.14 (s, 1H).

Step 2 6-(2,3-Difluoro-4-formyl-phenoxy)-nicotinonitrile

Combine 2,3-difluoro-4-hydroxy-benzaldehyde (see Canadian patent1190093) (1.93 g, 12.2 mmol), 6-chloronicotinonitrile (1.69 g, 12.2mmol), K₂CO₃ (2.53 g, 18.3 mmol) and DMA (30 ml) in a sealed, pressurevessel. Heat the suspension at 180° C. for five minutes in a microwave(600 Watts), cool to near ambient temperature and pour into aqueousNH₄Cl. Extract aqueous with EtOAc (2×), wash with water (2×) and brine,dry (MgSO₄) and concentrate. Purify on silica gel (20% EtOAc/Hexane) togive 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g) as awhite solid. ¹HNMR (CDCl₃): 10.33 (s, 1H), 8.42 (s, 1H), 8.02 (d, 1H),7.73 (t, 1H), 7.20 (d, 1H), 7.15 (t, 1H).

Step 3 6-(2,3-Difluoro-4-formyl-phenoxy)-nicotinamide

Add 30% aq. H₂O₂ (7.95 ml) to a suspension of6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g, 7.95 mmol),K₂CO₃ (550 mg, 3.98 mmol) and DMSO (20 ml) stirring in an ice/waterbath. After one hour, pour the reaction mixture into water and extractwith EtOAc. Wash the extract with water and brine before drying (MgSO₄)and concentrating to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide(1.64 g) as a white solid. ¹HNMR (DMSO-d₆): 10.14 (s, 1H), 8.58 (s, 1H),8.33 (d, 1H), 8.07 (s, 1H), 7.74 (t, 1H), 7.55 (s, 1H), 7.33 (d, 1H),7.27 (t, 1H).

Step 4

Combine 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00mmol), n-pentylamine (105 mg, 1.20 mmol), and MeOH (3 ml) in a roundbottom flask equipped with nitrogen inlet and stir for two hours. AddNaBH₄ (57 mg, 1.50 mmol) and stir for an additional two hours beforeconcentrating. Dissolve concentrate in EtOAc and wash with 5% aq. KOHand brine, dry (Na₂SO₄), and concentrate. Purify on silica gel (5% (1 MNH₃/MeOH)/DCM) to give the title compound (290 mg) as a white solid.Mass spectrum (ion spray): m/z=350 (M+1); ¹H NMR (DMSO-d₆): 8.55 (s,1H), 8.28 (d, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.22 (d,1H), 7.15 (m, 1H), 3.73 (s, 2H), 2.48 (t, 2H), 1.41 (m, 2H), 1.25 (m,4H), 0.84 (m, 3H).

EXAMPLE 7116-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-6-methoxy-phenoxy}-nicotinamide

Step 1 6-(2-Fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide

Using a method similar to Example 710, Step 2, using3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (Journal of Organic Chemistry(1986), 51(21), 4072-3.) (2.84 g, 16.7 mmol), 6-chloronicotinonitrile(2.31 g, 16.7 mmol) and K₂CO₃ (3.46 g, 25.0 mmol) gives6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinonitrile (3.04 g) as awhite solid.

¹H NMR (CDCl₃): 9.94 (s, 1H), 8.37 (s, 1H), 7.98 (d, 1H), 7.36 (m, 2H),7.20 (d, 1H), 3.87 (s, 3H).

Hydrolysis of 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinonitrile(3.04 g, 11.1 mmol) in a similar manner as described for Example 710,Step 3, gives 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide (2.75g) as a white solid. ¹H NMR (DMSO-d₆): 9.96 (s, 1H), 8.50 (s, 1H), 8.28(d, 1H), 8.01 (s, 1H), 7.55 (m, 2H), 7.48 (s, 1H), 7.26 (d, 1H), 3.82(s, 3H).

Step 2

Using a method similar to Example 710, Step 4, using6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide (250 mg, 0.861mmol), 3,3-dimethyl-butylamine (104 mg, 1.03 mmol), and NaBH₄ (49 mg,1.29 mmol) gave the title compound (259 mg) as a white solid. Massspectrum (ion spray): m/z=376 (M+1);

¹H NMR (DMSO-d₆): 8.50 (s, 1H), 8.23 (d, 1H), 7.98 (s, 1H), 7.44 (s,1H), 7.13 (d, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 3.71 (s, 3H), 3.68 (s,2H), 2.51 (t, 2H), 1.37 (t, 2H), 0.86 (s, 9H).

EXAMPLE 7126-{4-[(3,3-Dimethyl-butylamino)-methyl]-2,6-difluoro-phenoxy}-nicotinamide

Step 1 6-(2,6-Difluoro-4-formyl-phenoxy)-nicotinamide

Using a method similar to Example 710, Step 2, using3,5-difluoro-4-hydroxy-benzaldehyde (Journal of Medicinal Chemistry(1989), 32(2), 450-5.) (2.50 g, 15.8 mmol), 6-chloronicotinonitrile(2.19 g, 15.8 mmol) and K₂CO₃ (3.27 g, 23.7 mmol) gives6-(4-formyl-2,6-difluoro-phenoxy)-nicotinonitrile (2.84 g) as a whitesolid. ¹H NMR (CDCl₃): 9.95 (s, 1H), 8.39 (s, 1H), 8.02 (d, 1H), 7.58(d, 2H), 7.25 (d, 1H).

Hydrolysis of 6-(4-formyl-2,6-difluoro-phenoxy)-nicotinonitrile (3.47 g,13.3 mmol) in a similar manner as described for Example 710, Step 3,gives 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (2.87 g) as a whitesolid. ¹H NMR (CDCl₃): 9.94 (s, 1H), 8.49 (s, 1H), 8.25 (d, 1H), 7.57(d, 2H), 7.20 (d, 1H), 5.85 (br. s, 2H).

Step 2

Using a method similar to Example 710, Step 4, using6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol),3,3-dimethylbutylamine (105 mg, 1.20 mmol), and NaBH₄ (57 mg, 1.50 mmol)gave the title compound (292 mg) as a white solid. Mass spectrum (ionspray): m/z=364 (M+1); ¹H NMR (DMSO-d₆): 8.54 (s, 1H), 8.30 (d, 1H),8.04 (s, 1H), 7.51 (s, 1H), 7.29 (d, 1H), 7.22 (d, 2H), 3.71 (s, 2H),2.49 (t, 2H), 1.36 (m, 2H), 0.86 (s, 9H).

EXAMPLE 7136-{2,6-Difluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 712, using6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (Example 712, Step 1)(139 mg, 0.500 mmol), isoamylamine (52 mg, 0.600 mmol), and NaBH₄ (28mg, 0.750 mmol) gave the title compound (148 mg) as a white solid. Massspectrum (ion spray): m/z=350 (M+1); ¹H NMR (CDCl₃): 8.51 (s, 1H), 8.21(d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 5.74 (br. s, 2H), 3.79 (s, 2H),2.65 (t, 2H), 1.66 (m, 1H), 1.41 (m, 2H), 0.91 (d, 6H).

EXAMPLE 7146-{2,3,6-Trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

Step 1

2,3,5-Trifluoro-4-hydroxy-benzaldehyde

Add hexamethylenetetramine (7.10 g, 50.6 mmol) portion wise to asolution of 2,3,6-trifluorophenol (5.00 g, 33.7 mmol) in TFA (35 ml) atambient temperature and reflux for 15 hours. After cooling, treat thereaction mixture with water (60 ml), followed by 50% aq. H₂SO₄ (30 ml),and stir at ambient temperature for 30 minutes. Extract with EtOAc (2×)and wash with 1N aq. HCl (3×) and water. Extract the organic with 2N aq.NaOH (2×) and acidify the alkaline extract with conc. HCl while coolingin an ice/water bath. Collect the resulting solid via filtration and dryto give 2,3,5-trifluoro-4-hydroxy-benzaldehyde (2.97 g) as an off-whitesolid.

Step 26-{2,3,6-Trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinonitrile

Using a method similar to Example 710, Part 2, using2,3,5-trifluoro-4-hydroxy-benzaldehyde (1.00 g, 5.64 mmol),6-chloronicotinonitrile (782 mg, 5.64 mmol) and K₂CO₃ (1.17 g, 8.47mmol) gives 6-(2,3,6-trifluoro-4-formyl-phenoxy)-nicotinonitrile (907mg) contaminated with 6-chloronicotinonitrile starting material.Dissolve this mixture in MeOH (15 ml) and treat with isoamylamine (194mg, 2.23 mmol). After stirring for two hours, add NaBH₄ (105 mg, 2.79mmol) and stir for an additional hour. Purification as described inExample 710, Step 4, gives6-{2,3,6-trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinonitrile(383 mg) as a colorless oil.

Step 3

Hydrolysis of6-{2,3,6-trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinonitrile(383 mg, 1.09 mmol) in a similar manner as described for Example 710,Step 3, gives the title compound (374 mg) as a white solid. Massspectrum (ion spray): m/z=368 (M+1); ¹HNMR (CDCl₃): 8.50 (s, 1H), 8.23(d, 1H), 7.16 (d, 1H), 7.08 (m, 1H), 5.83 (br. s, 2H), 3.87 (s, 2H),2.66 (t, 2H), 1.64 (m, 1H), 1.41 (m, 2H), 0.90 (d, 6H).

EXAMPLE 7156-{3-[(2-Cyclohexyl-ethylamino)-methyl]-2-methyl-phenoxy}-nicotinamide

Step 1

6-(3-Formyl-2-methyl-phenoxy)-nicotinamide

Using a method similar to Example 221, Step 1, using2-methyl-3-hydroxy-benzaldehyde (see European Patent 0807621 A1) (965mg, 6.42 mmol), 6-chloronicotinonitrile (890 mg, 6.42 mmol) and K₂CO₃(1.33 g, 9.63 mmol) gives 6-(3-formyl-2-methyl-phenoxy)-nicotinonitrile(1.40 g) as a white solid. ¹H NMR (CDCl₃): 10.30 (s, 1H), 8.41 (s, 1H),7.96 (d, 1H), 7.78 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 7.10 (d, 1H),2.45 (s, 3H).

Hydrolysis of 6-(3-formyl-2-methyl-phenoxy)-nicotinonitrile (1.40 g,5.55 mmol) in a similar manner as described for Example 710, Step 3,gives 6-(3-formyl-2-methyl-phenoxy)-nicotinamide (1.27 g) as a whitesolid. ¹H NMR (CDCl₃): 10.31 (s, 1H), 8.52 (s, 1H), 8.21 (d, 1H), 7.76(d, 1H), 7.44 (t, 1H), 7.32 (d, 1H), 7.04 (d, 1H), 5.77 (br. s, 2H),2.47 (s, 3H).

Step 2

Using a method similar to Example 710, Step 4, using6-(3-formyl-2-methyl-phenoxy)-nicotinamide (256 mg, 1.00 mmol),cyclohexylethylamine (Synthesis (1983), (5), 388-9) (190 mg, 1.50 mmol),and NaBH₄ (57 mg, 1.50 mmol) gave the title compound (325 mg) as a whitesolid. Mass spectrum (ion spray): m/z=368 (M+1);

¹H NMR (DMSO-d₆): 8.54 (s, 1H), 8.21 (d, 1H), 7.98 (s, 1H), 7.43 (s,1H), 7.22-7.14 (m, 2H), 7.00 (d, 1H), 6.92 (d, 1H), 3.65 (s, 2H), 2.53(t, 2H), 2.00 (s, 3H), 1.66-1.55 (m, 5H), 1.35-1.27 (m, 3H), 1.20-1.06(m, 3H), 0.84 (m, 2H).

EXAMPLE 716 6-[2-Isopropyl-3-(2-pentylamino-ethyl)-phenoxy]-nicotinamide

Step 1

2-Isopropyl-3-methoxy-benzaldehyde

Add drop wise a 1 M DIBAL-H/toluene solution (122 mmol) over two hours,to a solution of 2-isopropyl-3-methoxy-benzonitrile (see JCS 13, 489,(1948)), (10.7 g, 61.0 mmol) in toluene (200 ml), stirring undernitrogen at −78° C. After the addition is complete, allow the reactionmixture to warm to 0° C. over two hours and maintain at 0° C. for anadditional two hours. Quench the reaction mixture by drop wise additionof AcOH (35 ml), followed by water (100 ml), and stir at ambienttemperature for two hours. Dilute with additional water (100 ml),separate layers, extract aqueous with EtOAc (2×), and wash combinedorganic with water (2×) and brine. After drying (Na₂SO₄) andconcentrating, purify crude on silica gel (10% EtOAc/hexane) to give2-isopropyl-3-methoxy-benzaldehyde (8.81 g) as a yellow oil. ¹H NMR(CDCl₃): 10.45 (s, 1H), 7.42 (d, 1H), 7.27 (t, 1H), 7.07 (d, 1H), 4.03(m, 1H), 3.85 (s, 3H), 1.39 (d, 6H).

Step 2

2-Isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene

Using a method similar to Example 659, Step 1, using2-isopropyl-3-methoxy-benzaldehyde (3.56 g, 20.0 mmol), nitromethane(3.25 ml, 60.0 mmol), ammonium acetate (2.00 g, 26.0 mmol) and aceticacid (25 ml) gave 2-isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene (3.92g) as a viscous oil. ¹H NMR (CDCl₃): 8.48 (d, 1H), 7.38 (d, 1H), 7.20(t, 1H), 7.02-6.96 (m, 2H), 3.84 (s, 3H), 3.41 (m, 1H), 1.36 (d, 6H).

Step 3

2-(2-Isopropyl-3-methoxy-phenyl)-ethylamine

Using a method similar to Example 659, Step 2, using2-isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene (3.92 g, 17.7 mmol), LAH(53.1 mmol) and AlCl₃ (53.1 mmol) gave2-(2-isopropyl-3-methoxy-phenyl)-ethylamine (3.4 g) as a viscous oil. ¹HNMR (CDCl₃): 7.08 (t, 1H), 6.77-6.73 (m, 2H), 3.80 (s, 3H), 3.22 (m,1H), 2.89 (m, 2H), 2.80 (m, 2H), 1.32 (d, 6H).

Step 4 [2-(3-Hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butylester

Add 1M BBr₃/DCM (44.2 mmol) drop wise, over 40 minutes, to a solution of2-(2-isopropyl-3-methoxy-phenyl)-ethylamine (3.4 g, 17.7 mmol) in DCM(40 ml) stirring at −78° C. under nitrogen. After addition is complete,stir at ambient temperature for two hours. Cool reaction mixture back to−78° C., quench with MeOH (25 ml) and concentrate. To this crudematerial, add THF (50 ml), 1M aq. K₂CO₃ (45 ml) and Boc₂O (4.24 g, 19.4mmol), and stir overnight at ambient temperature. After pouring thereaction mixture into aq. NH₄Cl, extract with EtOAc, wash extract withbrine, dry (Na₂SO₄) and concentrate. Purify crude on silica gel (10% to40% EtOAc/hexane) to give[2-(3-hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butyl ester(4.02 g) as a viscous, amber oil. ¹H NMR (CDCl₃): 6.97 (t, 1H), 6.70 (d,1H), 6.58 (d, 1H), 4.58 (br. s, 1H), 3.30 (m, 2H), 3.23 (m, 1H), 2.83(t, 2H), 1.44 (s, 9H), 1.37 (d, 6H).

Step 5{2-[3-(5-Cyano-pyridin-2-yloxy)-2-isopropylphenyl]-ethyl}-carbamic acidtert-butyl ester

Using a method similar to Example 221, Step 1, using[2-(3-hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butyl ester(4.02 g, 14.4 mmol), 6-chloronicotino-nitrile (1.99 g, 14.4 mmol) andK₂CO₃ (2.98 g, 21.5 mmol) gives{2-[3-(5-cyano-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamic acidtert-butyl ester (4.11 g) as a yellow foam. ¹H NMR (CDCl₃): 8.50 (s,1H), 7.92 (d, 1H), 7.17 (t, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.86 (d,1H), 4.63 (br. s, 1H), 3.34 (m, 2H), 3.27 (m, 1H), 2.91 (t, 2H), 1.44(s, 9H), 1.24 (d, 6H).

Step 6{2-[3-(5-Carbamoyl-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamicacid tert-butyl ester

Hydrolysis of{2-[3-(5-cyano-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamic acidtert-butyl ester (4.11 g, 10.7 mmol) in a similar manner as describedfor Example 710, Step 3, gives{2-[3-(5-Carbamoyl-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamicacid tert-butyl ester (4.30 g) as a yellow foam. ¹H NMR (CDCl₃): 8.63(s, 1H), 8.18 (d, 1H), 7.15 (t, 1H), 7.03 (d, 1H), 6.95 (d, 1H), 6.86(d, 1H), 5.98 (br. s, 2H), 4.67 (br. s, 1H), 3.34 (m, 2H), 3.26 (m, 1H),2.90 (t, 2H), 1.44 (s, 9H), 1.26 (d, 6H).

Step 7 6-[3-(2-Amino-ethyl)-2-isopropyl-phenoxy]-nicotinamide

Deprotection of{2-[3-(5-Carbamoyl-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamicacid tert-butyl ester (4.30 g, 10.7 mmol) as described in Example 651,Step 6, gave 6-[3-(2-amino-ethyl)-2-isopropyl-phenoxy]-nicotinamide(2.72 g) as a white foam.

¹H NMR (DMSO-d₆): 8.59 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.44 (s,1H), 7.11 (t, 1H), 7.03-6.98 (m, 2H), 6.80 (d, 1H), 3.24 (m, 1H), 2.71(m, 4H), 1.72 (br. s, 2H), 1.17 (d, 6H).

Step 8

Using a method similar to Example 710, Step 4, using6-[3-(2-amino-ethyl)-2-isopropyl-phenoxy]-nicotinamide (299 mg, 1.00mmol), valeraldehyde (112 mg, 1.30 mmol), and NaBH₄ (57 mg, 1.50 mmol)gave the title compound (245 mg) as a colorless glass. Mass spectrum(ion spray): m/z=370 (M+1); ¹H NMR (DMSO-d₆): 8.59 (s, 1H), 8.22 (d,1H), 8.00 (s, 1H), 7.44 (s, 1H), 7.10 (t, 1H), 7.01 (m, 2H), 6.80 (d,1H), 3.24 (m, 1H), 2.76 (m, 2H), 2.63 (m, 2H), 2.50 (m, 2H), 1.38 (m,2H), 1.25 (m, 4H), 1.16 (d, 6H), 0.84 (t, 3H).

EXAMPLE 7176-(2-Methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.100 g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(3.6 mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions)and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 5 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 10 g ISCO® columnwith 6% to 15% (2.0 M NH₃ in methanol) in ethyl acetate to give6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide(0.0958 g, 65.6%). Dissolve the compound in dichloromethane (2.5 mL) andadd 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stirthe solution for a short time before concentrating to afford the titlecompound: TOF MS ES⁺ 398.2 (M+H)⁺, HRMS calcd for C₂₃H₃₂N₃O₃ 398.2444(M+H)⁺, found 398.2440, time 0.52 min; Anal. Calcd forC₂₃H₃₁N₃O₃.0.5H₂O: C, 57.35; H, 7.22; N, 8.36. Found: C, 57.33; H, 6.94;N, 8.34.

EXAMPLE 7186-(4-{[2-(2,4-Difluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamidemethanesulfonate

To a slurry of LiAlH₄ (0.417 g, 11.0 mmol) in THF (25 mL), add AlCl₃(1.47 g, 11.0 mmol) in THF (10 mL). Cool the reaction mixture to 0° C.and slowly add 2,4-difluorophenylacetonitrile (0.11 g, 6.53 mmol).Quench with saturated aqueous Na₂CO₂ (10 mL) and filter through aCelite® pad. Dilute the filtrate to 150 mL with dichloromethane. Extractthe product out with 1.0 N HCl (2×100 mL). Add 5.0 N NaOH to the aqueouslayer until it is basic. Extract the aqueous layer with dichloromethane(2×100 mL), dry the organic layer over Na₂SO₄, filter and concentrate toafford the 2-(2,4-difluorophenyl)ethylamine as the crude amine.

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.300 g, 1.10 mmol), 2-(2,4-difluorophenyl)ethylamine (0.343 g, 2.184mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(4.4 mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions)and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 2% to 20% (2.0 M NH₃ in methanol) in ethyl acetate to give6-(4-{[2-(2,4-difluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide.Dissolve the compound in methanol (5.0 mL) and add 1 equivalent of 0.50M methanesulfonic acid in dichloromethane. Stir the solution for a shorttime before concentrating to give the title compound: TOF MS ES⁺ 414.2(M+H)⁺, HRMS calcd for C₂₂H₂₂N₃O₃F₂ 414.1629 (M+H)⁺, found 414.1613,time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18 min], t_(R)=11.6 min, 100% purity.

EXAMPLE 7195-(2-Methoxy-4-pentylaminomethylphenoxy)pyrazine-2-carboxamide

Part A: 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide

Dissolve 5-chloropyrazine-2-carboxamide (Example 387, Part A) (0.374 g,2.34 mmol) and vanillin (0.361 g, 2.34 mmol) in DMF (23.7 mL). Add K₂CO₃(0.821 g, 8.94 mmol) and heat at 100° C. for 1.5 hours. Concentrate thereaction mixture. Take the solid up in water (50 mL) and extract withdichloromethane (3×100 mL). Dry the organic layer over Na₂SO₄, filterand concentrate to give the title compound (0.625 g, 96.4%): TOF MS ES⁺274.1 (M+H)⁺, HRMS calcd for C₁₃H₁₂N₃O₄ 274.0828 (M+H)⁺, found 274.0829,time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 19 min],t_(R)=10.2 min, 98.1% purity.

Part B: 5-(2-Methoxy-4-pentylaminomethylphenoxy)pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.200 g, 0.732 mmol), amylamine (0.0670 g, 0.769 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), capand stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 60% to90% (5% (2.0 M NH₃ in methanol) in ethyl acetate) in hexanes.Concentrate the fractions containing the product. Take the solid up inethyl acetate (50 mL) and wash with 1.0 N NaOH to give the titlecompound (0.180 g, 71.7%): TOF MS ES⁺ 345.2 (M+H)⁺, HRMS calcd forC₁₈H₂₅N₄O₃ 345.1927 (M+H)⁺, found 345.1926, time 0.52 min; HPLC [WatersXTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 23 min], t_(R)=10.4 min, 100%purity.

EXAMPLE 7205-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide

Place 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine(0.0993 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in avial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH₄ (ca. 3-5eq in two portions) and stir until the gasses stop evolving. Load thereaction mixture directly onto a 25 g ISCO® pre-load column. Dry thecolumn in a vacuum oven at room temperature. Purify by eluting through a40 g ISCO® column 5% to 20% (2.0 M NH₃ in methanol) in ethyl acetate.Concentrate the fractions containing the product. Take the solid up inethyl acetate (50 mL) and wash with 1.0 N NaOH to give the titlecompound (0.168 g, 59.4%): TOF MS ES⁺ 387.2031 (M+H)⁺, HRMS calcd forC₂₀H₂₇N₄O₄ 387.2032 (M+H)⁺, found 387.2031, time 0.52 min; HPLC [WatersXTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1%TFA/water at 1.0 mL/min, 5-95% over 23 min], t_(R)=8.7 min, 100% purity.

EXAMPLE 7216-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyridazine-3-carboxamide

Part A: Methyl 6-chloropyridazine-3-carboxylate

Dissolve 6-oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate (33.0g, 209 mmol) in SOCl₂ (700 mL) and reflux for 2.5 hours. Concentrate thedark solution to complete dryness. Take the solid up in dichloromethane(700 mL), cool to 0° C. and add methanol (9.6 mL) and triethylamine(54.5 mL). Allow the reaction mixture to warm to room temperature as itstirs overnight. Load the reaction mixture onto a silica gel plug. Washthe plug with 20% ethyl acetate in dichloromethane. Purify the impurefractions by chromatography eluting with 50% ethyl acetate indichloromethane to give the title compound (29.4 g, 82%): TOF MS ES⁺173.0 (M+H)⁺, HRMS calcd for C₆H₆N₂O₂Cl 173.0118 (M+H)⁺, found 173.0130,time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18], t_(R)=6.9 min, 100% purity.

Part B: 6-Chloropyridazine-3-carboxamide

Dissolve methyl 6-chloropyridazine-3-carboxylate (0.498 g, 2.89 mmol) inmethanol (28 mL). Cool the solution to 0° C. with an acetone/dry icebath. Bubble ammonia into the reaction mixture, then allow it to warm to0° C. over 1 hour before concentrating to give the title compound (0.451g, 99%): TOF MS ES⁺ 157.0 (M)⁺, HRMS calcd for C₅H₄N₃OCl 157.0043 (M)⁺,found 157.0010, time 4.45 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.1 TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20%over 5 min then 20-95% over 18], t_(R)=5.2 min, 100% purity.

Part C: 6-(4-Formyl-2-methoxyphenoxy)pyridazine-3-carboxamide

Dissolve 5-chloropyradizine-2-carboxamide (Example 721, Part B) (0.502g, 3.18 mmol) and vanillin (0.484 g, 3.18 mmol) in DMF (16 mL). AddK₂CO₃ (1.10 g, 7.96 mmol) and heat at 100° C. for 3.6 hours. Concentratethe reaction mixture. Take the solid up in water (100 mL) and extractwith dichloromethane (3×100 mL). Dry the organic layer over MgSO₄,filter and concentrate to give the title compound (0.824 g, 95%): TOF MSES⁺ 274.1 (M+H)⁺, HRMS calcd for C₁₃H₁₂N₃O₄ 274.0828 (M+H)⁺, found274.0832, time 0.59 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95over 19 min], t_(R)=11.4 min, 96.3% purity.

Part D:6-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyridazine-3-carboxamide

Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example721, Part C) (0.200 g, 0.732 mmol), isoamylamine (0.0670 g, 0.769 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 10%to 20% (2.0 M NH₃ in methanol) in ethyl acetate. Concentrate thefractions containing the product. Take the solid up in ethyl acetate (50mL) and wash with 1.0 N NaOH (2×10 mL). Dry the organic layer overNa₂SO₄, filter and concentrate to give the title compound (0.112 g,44%): TOF MS ES⁺ 345.2 (M+H)⁺, HRMS calcd for C₁₈H₂₅N₄O₃ 345.1927(M+H)⁺, found 345.1926, time 0.52 min; Anal. Calcd for C₁₈H₂₄N₄O₃: C,62.77; H, 7.02;, N, 16.27. Found: C, 62.29; H, 7.01; N, 15.50.

EXAMPLE 7226-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridazine-3-carboxamide

Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example721, Part C) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine(0.0993 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in avial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH₄ (ca. 3-5eq in two portions) and stir until the gasses stop evolving. Load thereaction mixture directly onto a 25 g ISCO® pre-load column. Dry thecolumn in a vacuum oven at room temperature. Purify by eluting through a40 g ISCO® column with 10% to 20% (2.0 M NH₃ in methanol) in ethylacetate. Concentrate the fractions containing the product. Take thesolid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2×10 mL).Dry the organic layer over Na₂SO₄, filter and concentrate to give thetitle compound (0.154 g, 54%): TOF MS ES⁺ 387.2 (M+H)⁺, HRMS calcd forC₂₀H₂₇N₄O₄ 387.2032 (M+H)⁺, found 387.2024, time 0.52 min; Anal. Calcdfor C₂₀H₂₆N₄O₄: C, 62.16; H, 6.78; N, 14.50. Found: C, 61.58; H, 6.66;N, 14.13.

EXAMPLE 723 6-(2-Methoxy-4-propylaminomethylphenoxy)nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), propylamine (0.060 g, 1.01 mmol) and 3 {acuteover (Å)} molecular sieves in a vial. Add methanol (6.1 mL), cap andstir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.327 g, 84%): TOF MS ES⁺ 316.2 (M+H)⁺, HRMScalcd for C₁₇H₂₂N₃O₃ 316.1661 (M+H)⁺, found 316.1671, time 0.52 min;HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min, then 20-95% over 18min], t_(R)=8.3 min, 100% purity.

EXAMPLE 724 6-[4-(Isobutylaminomethyl)-2-methoxyphenoxy]nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), isobutylamine (0.074 g, 1.01 mmol) and 3 {acuteover (Å)} molecular sieves in a vial. Add methanol (6.1 mL), cap andstir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.344 g, 87%): TOF MS ES⁺ 330.2 (M+H)⁺, HRMScalcd for C₁₈H₂₄N₃O₃ 330.1818 (M+H)⁺, found 330.1808, time 0.52 min;HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min. then 20-95% over 18min], t_(R)=9.2 min, 100% purity.

EXAMPLE 7256-{4-[(2,2-Dimethylpropylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), neopentylamine (0.074 g, 1.01 mmol) and 3 {acuteover (Å)} molecular sieves in a vial. Add methanol (6.1 mL), cap andstir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to20% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto afford the title compound (0.339 g, 89%): TOF MS ES⁺ 344.2 (M+H)⁺,HRMS calcd for C₁₉H₂₆N₃O₃ 344.1974 (M+H)⁺, found 344.1963, time 0.52min; HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min,then 20-95% over 18 min], t_(R)=9.9 min, 99.2% purity.

EXAMPLE 7266-(2-Methoxy-4-{[(tetrahydropyran-4-ylmethyl)amino]methyl}phenoxy)nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 4-aminomethyltetrahydropyran (0.116 g, 1.01 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 15% (2.0 M NH₃ in methanol) in ethyl acetate to give the titlecompound as a free base. Dissolve the product in methanol and add oneequivalent of 0.5 M methanesulfonic acid solution in dichloromethane.Concentrate to give the title compound (0.375 g, 85%): TOF MS ES⁺ 372.2(M+H)⁺, HRMS calcd for C₂₀H₂₆N₃O₄ 372.1923 (M+H)⁺, found 372.1909, time0.50 min; HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min,then 20-95% over 18 min], t_(R)=8.3 min, 100% purity.

EXAMPLE 727 6-(4-Heptylaminomethyl-2-methoxyphenoxy)nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), heptylamine (0.060 g, 1.01 mmol) and 3 {acuteover (Å)} molecular sieves in a vial. Add methanol (6.1 mL), cap andstir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.341 g, 79%): TOF MS ES⁺ 372.2 (M+H)⁺, HRMScalcd for C₂₁H₃₀N₃O₃ 372.2287 (M+H)⁺, found 372.2294, time 0.52 min;HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min, then 20-95% over 18min], t_(R)=12.7 min, 99.0% purity.

EXAMPLE 7286-{2-Methoxy-4-[(2-pyridin-4-ylethylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g 0.918 mmol), 2-pyridin-4-ylethylamine (0.060 g, 1.01 mmol) and3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1 mL),cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to25% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.339 g, 76%): TOF MS ES⁺ 379.2 (M+H)⁺, HRMScalcd for C₂₁H₂₃N₄O₃ 379.1770 (M+H)⁺, found 379.1753, time 0.32 min; IR(KBr) 3418 (N—H), 1194 (O—CH₃), 1668 (C═O), 1610 (H₂NCO—) cm⁻¹.

EXAMPLE 7296-{2-Methoxy-4-[(3-methoxypropylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 3-methoxypropylamine (0.090 g, 1.01 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (6.1 mL), capand stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.328 g, 82%): TOF MS ES⁺ 346.2 (M+H)⁺, HRMScalcd for C₁₈H₂₄N₃O₄ 346.1767 (M+H)⁺, found 346.1766, time 0.52 min;HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 23 min],t_(R)=7.7 min, 100% purity.

EXAMPLE 7306-{4-[(3-Ethoxypropylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 3-ethoxypropylamine (0.060 g, 1.01 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (6.1 mL), capand stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.325 g, 82%): TOF MS ES⁺ 360.2 (M+H)⁺, HRMScalcd for C₁₉H₂₆N₃O₄ 360.1923 (M+H)⁺, found 360.1920, time 0.52 min;HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min, then 20-95% over 18min], t_(R)=9.3 min, 100% purity.

EXAMPLE 7316-{4-[(3-Isopropoxypropylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 3-isopropoxypropylamine (0.060 g, 1.01 mmol) and3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1 mL),cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and add one equivalentof 0.5 M methanesulfonic acid solution in dichloromethane. Concentrateto give the title compound (0.353 g, 84%): TOF MS ES⁺ 374.2 (M+H)⁺, HRMScalcd for C₂₀H₂₈N₃O₄ 374.2080 (M+H)⁺, found 374.2080, time 0.52 min;HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min, then 20-95% over 18min], t_(R)=10.1 min, 100% purity.

EXAMPLE 7326-{4-[(2-Isopropoxyethylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 2-aminoethyl isopropyl ether (0.060 g, 1.01 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 15% (2.0 M NH₃ in methanol) in ethyl acetate to give the titlecompound as a free base. Dissolve the product in methanol and add oneequivalent of 0.5 M methanesulfonic acid solution in dichloromethane.Concentrate to give the title compound (0.333 g, 81%): TOF MS ES⁺ 360.2(M+H)⁺, HRMS calcd for C₁₉H₂₆N₃O₄ 360.1923 (M+H)⁺, found 360.1939, time0.52 min; HPLC [YMC-Pro Pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min,then 20-95% over 18 min], t_(R)=9.7 min, 99.2% purity.

EXAMPLE 7336-{4-[(3-Ethylpentylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Part A: 3-Ethylpentanenitrile

To a suspension of sodium cyanide (3.33 g, 67.8 mmol) in DMSO (24 mL) at60° C., slowly add 1-bromo-2-ethylbutane (10 g, 60.6 mmol). Keep theinternal temperature between 55-60° C. by intermittently cooling with anice bath. Add additional DMSO (10 mL) to keep the slurry stirring. Heatat 70° C. for two hours, then cool to room temperature. Dilute thereaction mixture with water (100 mL) and extract with ether (3×50 mL).Wash the organic extracts with 5.0 N HCl (1×25 mL) and water (1×25 mL).Dry the organic layer over MgSO₄, filter and concentrate to give thetitle compound (6.43 g, 96%): ¹H NMR (CDCl₃, 400 MHz) δ 2.34 (d, J=6.2Hz, 2H), 1.56 (m, 1H), 1.46 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).

Part B: 3-Ethylpentylamine

Cool a slurry of LiAlH₄ (4.35 g, 115 mmol) in ether (57 mL) to 0° C.Allow reaction mixture to gently reflux upon the addition of3-ethylpentanenitrile (6.38 g, 57.3 mmol). Stir for two hours beforequenching with 1.0 N NaOH. Filter the suspension through a Celite® pad.Separate the two layers and wash the organic layer with additional 1.0 NNaOH (2×25 mL), dry it over Na₂SO₄, filter and carefully concentrate togive the title compound: ¹H NMR (DMSO-d₆, 400 MHz) δ 2.50 (t, J=7.3 Hz,2H), 1.24 (m, 7H). 0.080 (t, J=7.0 Hz, 6H).

Part C: 6-{4-[(3-Ethylpentylamino)methyl]-2-methoxyphenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 3-ethylpentylamine (0.111 g, 0.964 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (6.1 mL), capand stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to15% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compoundas a free base. Dissolve the product in methanol and dichloromethane andadd one equivalent of 0.5 M methanesulfonic acid solution indichloromethane. Concentrate to give the title compound (0.371 g, 84%):TOF MS ES⁺ 372.2 (M+H)⁺, HRMS calcd for C₂₁H₃₀N₃O₃ 372.2287 (M+H)⁺,found 372.2271, time 0.32 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm,S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 23 min], t_(R)=11.9 min, 100% purity.

EXAMPLE 7346-{2-Methoxy-4-[(2-morpholin-4-ylethylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 2-morpholin-4-ylethylamine (0.126 g, 0.964 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 30% (2.0 M NH₃ in methanol) in ethyl acetate to give the titlecompound as a free base. Dissolve the product in methanol and add oneequivalent of 0.5 M methanesulfonic acid solution in dichloromethane.Concentrate to give the title compound (0.350 g, 74%): TOF MS ES⁺ 387.2(M+H)⁺, HRMS calcd for C₂₀H₂₇N₄O₄ 387.2032 (M+H)⁺, found 387.2032, time0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 23 min],t_(R)=5.7 min, 100% purity.

EXAMPLE 7356-{2-Methoxy-4-[(2-thiomorpholin-4-ylethylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 2-thiomorpholin-4-ylethylamine (0.141 g, 0.964mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(6.1 mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions)and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 5% to 25% (2.0 M NH₃ in methanol) in ethyl acetate to give thetitle compound as a free base. Dissolve the product in methanol and addone equivalent of 0.5 M methanesulfonic acid solution indichloromethane. Concentrate to give the title compound (0.356 g, 73%):TOF MS ES⁺ 403.2 (M+H)⁺, HRMS calcd for C₂₀H₂₇N₄O₃S 403.1804 (M+H)⁺,found 403.1801, time 0.43 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm,S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min,5-95% over 23 min], t_(R)=6.2 min, 100% purity.

EXAMPLE 7366-{2-Methoxy-4-[(3-morpholin-4-ylpropylamino)methyl]phenoxy}nicotinamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B)(0.250 g, 0.918 mmol), 3-morpholin-4-ylpropylamine (0.139 g, 0.964 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (6.1mL), cap and stir overnight. Add NaBH₄ (ca. 3-5 eq in two portions) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by elating through a 40 g ISCO® column with 5%to 30% (2.0 M NH₃ in methanol) in ethyl acetate to give the titlecompound as a free base. Dissolve the product in methanol and add oneequivalent of 0.5 M methanesulfonic acid solution in dichloromethane.Concentrate to give the title compound (0.340 g, 74%): TOF MS ES⁺ 401.2(M+H)⁺, HRMS calcd for C₂₁H₂₉N₄O₄ 401.2189 (M+H)⁺, found 401.2178, time0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 23 min],t_(R)=5.6 min. 100% purity.

EXAMPLE 7375-{4-[(3,3-Dimethylbutylamino)methyl]-2-fluorophenoxy}pyrazine-2-carboxamide

Part A: 3-Fluoro-4-triisopropylsilanyloxybenzaldehyde

Add triisopropylsilyl chloride (74.32 g, 0.3855 mol), followed by DMF(25 mL), to a solution of 3-fluoro-4-hydroxybenzaldehyde (45.01 g,0.3213 mol) and imidazole (43.74 g, 0.6425 mole) in DMF (313 mL) at25-29° C. in a steady stream over 2 min. Stir for 1 hr at roomtemperature till the reaction complete as determined by HPLC (Column:4.6 mm×25 cm Zorbax RX-C8; eluent: 50/50 0.1% TFA:acetonitrile; flowrate 2 mL/min; detector: 230 nm; temperature: 22° C.; injection: 10 μL).Pour the reaction mixture into saturated aqueous ammonium chloridesolution (1 L) and extract with ether (3×1 L). Combine the ether layers,wash with brine (2×750 mL) and dried over sodium sulfate. Filter andconcentrate to give a yellow oil (106.3 g). Purify the crude oil on 1 kgMerck silica gel grade 60 with 20:1 heptane/ethyl acetate (90.14 g,94.6%).

Part B: (4-[1,3]Dioxolan-2-yl-2-fluorophenoxy)triisopropylsilane

Into a 5 L 3-neck flask equipped with a condenser and a Dean-Stark trapadd 3-fluoro-4-triisopropylsilanyloxybenzaldehyde (Example 737, Part A)(90.14 g, 0.3041 mol), ethylene glycol (188.75 g, 3.041 mol), andp-toluenesulfonic acid (0.58 g, 0.003041 mol) in toluene (3.155 L). Beatto boil and reflux until 130 mL of H₂O (lower layer) is collected in theDean-Stark trap (5 hrs). Cool to room temperature, wash with 10% aqueouspotassium carbonate solution (2×1 L) and brine (2×1 L), and dry oversodium sulfate. Filter and concentrate to give the crude product.

Part C: 4-[1,3]Dioxolan-2-yl-2-fluorophenol

To a solution of(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)triisopropylsilane (Example 93,Part B) (105.9 g, approximately 0.311 mol) in THF (1.589 L) add 1.0 Mtetrabutylammonium fluoride (TBAF) in THF (311 mL) in a steady streamover 5 min at 23-27° C. without cooling. Stir for 1 hr till the reactioncomplete by TLC (19:1 heptane/ethyl acetate). Concentrate to a red oiland partition between ether (500 mL) and deionized water (1 L). Separatethe layers and extract the aqueous layer with ether (500 mL). Combinethe ether layers, wash with brine and dry over sodium sulfate. Filterand concentrate to give the crude product (92.9 g. Dissolve the crudeproduct in dichloromethane and filter through 400 g of silica gel 60.Wash with dichloromethane (3×1 L fractions) and concentrate the combinedfiltrate to give an impure product. Crystallize fromdichloromethane/heptane to give the title compound (29.8 g, 52%). Gaschromatography: retention time 15.96 min (30 m×0.32 mm i.d. DB-1 column,0.25 micron film thickness; 1.2 mL/min flow rate; 55:1 split ratio;temperature profile: 35° C./3 min, 10° C. temperature increase per min;250° C./10.5 min). ¹H NMR (DMSO-d₆) δ 3.84-3.93 (m, 2H, CH₂), 3.93-4.04(m, 2H, CH₂), 5.60 (s, 1H, CH), 6.91 (t, 1H, ArH), 7.06 (dd, 1H, ArH),7.15 (dd, 1H, ArH), 10.0 (s, 1H, OH).

Part D: 5-(4-[1,3]Dioxolan-2-yl-2-fluorophenoxy)pyrazine-2-carboxamide

Heat a mixture of 5-chloropyrazine-2-carboxamide (14.18 g, 0.09 mol)(see S. Fujii, T. Takagi, S. Toshihlisa, M. Seki, Agric. Biol. Chem.,1982, 46, (8), 2169), 4-[1,3]dioxolan-2-yl-2-fluorophenol (Example 737,Part C) (16.58 g, 0.09 mole), and powdered potassium carbonate (31.10 g,0.225 mol) in DMF (213 mL) at 100° C. for 2 hours. Dilute the reactionmixture to 1 L with deionized water, filter at room temperature, andwash the filter cake with water. Extract the filtrate with ether (2×1 L)and dry the extracts over sodium sulfate. Combine the filter cake andether extracts and concentrate to dryness to give a semi-solid (32.81 g)containing residual water and DMF (by ¹H NMR). Recrystallize a portionfrom ethyl acetate to give a purified sample: mp 169-172° C.; ¹H NMR(DMSO-d₆) δ 3.94-4.03 (m, 2H, CH₂), 4.03-4.11 (m, 2H, CH₂), 5.78 (s, 1H,CH), 7.36 (d, 1H, ArH), 7.46 (t, 2H, ArH), 7.73 (s, 1H, HetH), 8.13 (s,1H, HetH), 8.68 (d, 2H, amide); ¹³C NMR (DMSO-d₆) δ 64.879, 101.364,114.869, 123.251, 123.762, 132.997, 137.855, 139.454, 140.340, 140.744,152.019, 154.475, 159.643, 164.135; MS (ES+): m/z 306.0 (M+H).

Part E: 5-(2-Fluoro-4-formylphenoxy)pyrazine-2-carboxamide

Combine formic acid (90%, 453 mL) and crude5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyrazine-2-carboxamide (Example737, Part D) (32.81 g, approximately 0.09 mole) and stir initially aclear yellow solution, which becomes a thick slurry in an hour at roomtemperature. Stir overnight at room temperature till the reactioncomplete by HPLC. Quench the reaction with deionized water (1 L) andextract with dichloromethane (4×4 L). Combine the extracts and mix withaqueous sodium bicarbonate solution. Concentrate on a rotary evaporatorto give a slurry of a solid in water (when the separation of layers notpossible). Extract the mixture with ethyl acetate (4×1 L) andconcentrate the combined extracts to a yellow solid (29.65 g). Formslurries successively four times with boiling methanol (1 L) and filterwhile hot. Combine the filter cakes and dissolve in enough boilingmethanol to give a clear solution. Concentrate the solution toapproximately 1 liter and allow to crystallize at 0° C. Filter theresulting slurry at 0° C. and dry the filter cake under vacuum at roomtemperature to give the title compound (17.79 g, 75.7%). ¹H NMR(DMSO-d₆) δ 7.70 (t, 1H, ArH), 7.78 (s, 1H, HetH), 7.86-7.93 (m, 2H,ArH), 8.14 (s, 1H, HetH), 8.73 (d, 2H, amide), 10.0 (s, 1H, CHO); ¹³CNMR (DMSO-d₆) δ 116.884, 124.606, 126.980, 133.186, 134.967, 140.765,144.016, 152.493, 154.974, 159.276, 164.057, 190.777; MS (ES+) m/z 262.3(M+H).

Part F:5-{4-[(3,3-Dimethylbutylamino)methyl]-2-fluorophenoxy}pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.350 g, 1.14 mmol), 3,3-dimethylbutylamine (0.19 g, 1.41 mmol)and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (9.7 mL)cap and stir overnight. Add NaBH₄ (0.053 g, 1.41 mmol) and stir untilthe gasses stop evolving. Filter the reaction mixture, then concentrate.Purify by eluting through a 40 g ISCO® column with 6% to 30% (2.0 M NH₃in methanol) in ethyl acetate to give the title compound (0.225 g, 49%):TOF MS ES⁺ 347.2 (M+H)⁺, HRMS calcd for C₁₈H₂₄N₄O₂F 347.1883 (M+H)⁺,found 347.1883, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18], t_(R)=10.9 min, 100% purity.

EXAMPLE 7385-(2-Fluoro-4-{[2-(2-fluoropbenyl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 2-fluorophenethylamine (0.382 g, 2.75mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12 mL), cap and stir overnight. Add NaBH₄ (slight excess) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to10% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compound(0.718 g, 75%): TOF MS ES⁺ 384.2 (M+H)⁺, HRMS calcd for C₂₁H₂₀N₃O₂F₂387.2032 (M+H)⁺, found 387.2032, time 0.52 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% Over 18], t_(R)=11.4 min, 100%purity.

EXAMPLE 7395-{2-Fluoro-4-[(4-methylpentylamino)methyl]phenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 4-methylpentylamino (Example 433, Part A)(0.278 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial.Add methanol (12 mL), cap and stir overnight. Add NaBH₄ (slight excess)and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 0% to 10% (2.0 M NH₃ in methanol) in ethyl acetate to give thetitle compound (0.470 g, 55%): TOF MS ES⁺ 346.2 (M+H)⁺, HRMS calcd forC₁₉H₂₅N₃O₂F 346.1931 (M+H)⁺, found 346.1922, time 0.48 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.6 min, 100% purity.

EXAMPLE 7405-{4-[(3,3-Dimethylbutylamino)methyl]-2-fluorophenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 3,3-dimethylbutylamine (0.278 g, 2.75mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12 mL), cap and stir overnight. Add NaBH₄ (slight excess) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to10% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compound(0.543 g, 63%): TOF MS ES⁺ 346.2 (M+H)⁺, HRMS calcd for C₁₉H₂₅N₃O₂F346.1931 (M+H)⁺, found 346.1921, time 0.48 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=11.3 min, 100%purity.

EXAMPLE 7415-{4-[(4,4-Dimethylpentylamino)methyl]-2-fluorophenoxy}pyridine-2-carboxamide

Part A: 4,4-Dimethylpentanenitrile

To a suspension of sodium cyanide (3.33 g, 67.8 mmol) in DMSO (34 mL) at60° C., slowly add 1-bromo-3,3-dimethylbutane (10 g, 60.6 mmol). Keepthe internal temperature between 55-65° C. by intermittently coolingwith an ice bath. Heat at 70° C. for 1.5 hours, then cool to roomtemperature. Dilute the reaction mixture with water (100 mL) and extractwith ether (3×50 mL). Wash the organic extracts with 5.0 N HCl (1×25 mL)and water (1×25 mL). Dry the organic layer over MgSO₄, filter andconcentrate to give the title compound (6.66 g, 98%): ¹H NMR (CDCl3, 400MHz) δ 2.29 (t, J=8.1 Hz, 2H), 1.63 (t, J=8.1 Hz, 2H), 0.94 (s, 9H).

Part B: 4,4-Dimethylpentylamine

Cool a slurry of LiAlH₄ (4.30 g, 113 mmol) in ether (57 mL) to −30° C.Allow reaction mixture to gently reflux upon the addition of4,4-dimethylpentanenitrile (6.29 g, 56.6 mmol). Heat at reflux for anadditional 45 minutes. Cool the reaction mixture to room temperaturebefore quenching with 1.0 N NaOH. Filter the suspension through aCelite® pad. Separate the two layers and wash the organic layer withadditional 1.0 N NaOH (2×25 mL), dry it over Na₂SO₄, filter andcarefully concentrate to give the title compound: ¹H NMR (CDCl3, 400MHz) δ 2.68 (m, 2H), 2.17 (bs, 2H), 1.44 (m, 2H) 1.18 (t, J=11.0 Hz,2H), 0.88 (s, 9H).

Part C:5-{4-[(4,4-Dimethylpentylamino)methyl]-2-fluorophenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 4,4-dimethylpentylamine (0.317 g, 2.75mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12 mL), cap and stir overnight. Add NaBH₄ (slight excess) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to10% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compound(0.248 g, 28%): TOF MS ES⁺ 360.2 (M+H)⁺, HRMS calcd for C₂₀H₂₇N₃O₂F360.2087 (M+H)⁺, found 360.2076, time 0.48 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=12.3 min, 98.2%purity.

EXAMPLE 7425-{4-[(3-Ethylpentylamino)methyl]-2-fluorophenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 3-ethylpentylamine (Example 733, Part B)(0.317 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial.Add methanol (12 mL), cap and stir overnight. Add NaBH₄ (slight excess)and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 0% to 10% (2.0 M NH₃ in methanol) in ethyl acetate to give thetitle compound (0.516 g, 58%): TOF MS ES⁺ 360.2 (M+H)⁺, HRMS calcd forC₂₀H₂₇N₃O₂F 360.2087 (M+H)⁺, found 360.2086, time 0.53 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.3 min, 100% purity.

EXAMPLE 7435-{4-[(2-Cyclopentylethylamino)methyl]-2-fluorophenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 2-cyclopentylethylamine (0.792 g, 2.75mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12 mL), cap and stir overnight. Add NaBH₄ (slight excess) and stiruntil the gasses stop evolving. Load the reaction mixture directly ontoa 25 g ISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to10% (2.0 M NH₃ in methanol) in ethyl acetate to give the title compound(0.0850 g, 10%): TOF MS ES⁺ 358.2 (M+H)⁺, HRMS calcd for C₂₀H₂₅N₃O₂F358.1931 (M+H)⁺, found 358.1925, time 0.48 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=11.8 min, 94.2%purity.

EXAMPLE 7445-{2-Fluoro-4-[(2-thiomorpholin-4-ylethylamino)methyl]phenoxy}pyridine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403,Part B) (0.650 g, 2.50 mmol), 2-thiomorpholin-4-ylethylamine (0.402 g,2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Addmethanol (12 mL), cap and stir overnight. Add NaBH₄ (slight excess) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 0%to 30% (2.0 M NH₃ in methanol) in ethyl acetate to give the titlecompound (0.792 g, 81%): TOF MS ES⁺ 391.2 (M+H)⁺, HRMS calcd forC₁₉H₂₄N₄O₂FS 391.1604 (M+H)⁺, found 391.1594, time 0.48 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=6.7 min, 100% purity.

EXAMPLE 7455-{2-Fluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-pyrazine-2-carboxylicacid amide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), isoamylamine (0.147 g, 1.68 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), capand stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes) to givethe title compound (0.225 g, 50%): TOF MS ES⁺ 333.2 (M+H)⁺, HRMS calcdfor C₁₇H₂₂N₄O₂F 333.1727 (M+H)⁺, found 333.1714, time 0.55 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=10.1 min, 100% purity.

EXAMPLE 7465-(2-Fluoro-4-pentylaminomethylphenoxy)pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), amylamine (0.147 g, 1.68 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), capand stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column 0% to 15%(2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes) to give thetitle compound (0.334 g, 66%): TOF MS ES⁺ 333.2 (M+H)⁺, HRMS calcd forC₁₇H₂₂N₄O₂F 333.1727 (M+H)⁺, found 333.1722, time 0.53 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=10.3 min, 96.8% purity.

EXAMPLE 7475-{4-[(4,4-Dimethylpentylamino)methyl]-2-fluorophenoxy}pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 4,4-dimethylpentylamine (0.194 g, 1.68mmol) (Example 97, Part B) and 3 {acute over (Å)} molecular sieves in avial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g,1.53 mmol) and stir until the gasses stop evolving. Load the reactionmixture directly onto a 25 g ISCO® pre-load column. Dry the column in avacuum oven at room temperature. Purify by eluting through a 40 g ISCO®column with 0% to 15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate inhexanes). Concentrate the fractions containing the product. Take thesolid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL)to give the title compound (0.314 g, 57%): TOF MS ES⁺ 361.2 (M+H)⁺, HRMScalcd for C₁₉H₂₆N₄O₂F 361.2040 (M+H)⁺, found 361.2042, time 0.55 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.0 min, 100% purity.

EXAMPLE 7485-{4-[(3-Ethylpentylamino)methyl]-2-fluorophenoxy}pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 3-ethylpentylamine (0.194 g, 1.68 mmol)(Example 733, Part B) and 3 {acute over (Å)} molecular sieves in a vial.Add methanol (7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53mmol) and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 0% to 15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes)to give the title compound (0.342 g, 62%): TOF MS ES⁺ 361.2 (M+H)⁺, HRMScalcd for C₁₉H₂₆N₄O₂F 361.2040 (M+H)⁺, found 361.2048, time 0.57 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.0 min, 96.9% purity.

EXAMPLE 7495-(2-Fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.217g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Addmethanol (7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53mmol) and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 0% to 30% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes)to give the title compound (0.385 g, 67%): TOF MS ES⁺ 375.2 (M+H)⁺, HRMScalcd for C₁₉H₂₄N₄O₃F 375.1832 (M+H)⁺, found 375.1847, time 0.53 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=8.6 min, 95.4% purity.

EXAMPLE 7505-(2-Fluoro-4-{[2-(4-fluoroplenyl)ethylamino]methyl}phenoxy)pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 4-fluorophenethylamine (0.234 g, 1.68mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 0%to 15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes).Concentrate the fractions containing the product. Take the solid up indichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give thetitle compound (0.383 g, 65%): TOF MS ES⁺ 385.1 (M+H)⁺, HRMS calcd forC₂₀H₁₉N₄O₂F₂ 385.1476 (M+H)⁺, found 385.1480, time 0.55 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.1 min, 100% purity.

EXAMPLE 7515-{2-Fluoro-4-[(2-thiophen-2-ylethylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 2-(2-thienyl)ethylamine (0.217 g, 1.68mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 0%to 15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes).Concentrate the fractions containing the product. Take the solid up indichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give thetitle compound (0.100 g, 18%): TOF MS ES⁺ 373.1 (M+H)⁺, HRMS calcd forC₁₈H₁₈N₄O₂FS 373.1135 (M+H)⁺, found 373.1150, time 0.48 min: HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=10.3 min. 100% purity.

EXAMPLE 752 5-(2-Fluoro-4-hexylaminomethylphenoxy)pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), hexylamine (0.170 g, 1.68 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), capand stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 0% to15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes) to givethe title compound (0.329 g, 62%); TOF MS ES⁺ 347.2 (M+H)⁺, HRMS calcdfor C₁₈H₂₄N₄O₂F 347.1883 (M+H)⁺, found 347.1897, time 0.57 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.4 min, 94.8% purity.

EXAMPLE 7535-(4-{[2-(3,4-Dichlorophenyl)ethylamino]methyl}-2-fluorophenoxy)pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 3,4-dichlorophenethylamine (0.320 g, 1.68mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 0%to 15% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes).Concentrate the fractions containing the product. Take the solid up indichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give thetitle compound (0.293 g, 44%): TOF MS ES⁺ 435.1 (M+H)⁺, HRMS calcd forC₂₀H₁₈N₄O₂FCl₂ 435.0791 (M+H)⁺, found 435.0815, time 0.53 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.8 min, 100% purity.

EXAMPLE 7545-{2-Fluoro-4-[(3-isopropoxypropylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737,Part E) (0.400 g, 1.53 mmol), 3-isopropoxypropylamine (0.197 g, 1.68mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(7.7 mL), cap and stir overnight. Add NaBH₄ (0.058 g, 1.53 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 0%to 30% (2.0 M NH₃ in methanol) in 80% (ethyl acetate in hexanes).Concentrate the fractions containing the product. Take the solid up indichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give thetitle compound (0.395 g, 71%): TOF MS ES⁺ 363.2 (M+H)⁺, HRMS calcd forC₁₈H₂₄N₄O₃F 363.1832 (M+H)⁺, found 363.1821, time 0.57 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=9.8 min, 100% purity.

EXAMPLE 7556-(4-{[2-(2-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamidemethanesulfonate

Dissolve6-(4-{[2-(2-fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide(Example 431) (0.701, 1.18 mmol) in methanol (4.4 mL) anddichloromethane (4.4 mL). Add 0.5 M methanesulfonic acid (3.54 mL, 1.18mmol) in dichloromethane. Stir for 10 minutes, then concentrate to givethe title compound (0.875 g, ˜100%): TOF MS ES⁺ 396.2 (M+H)⁺, HRMS calcdfor C₂₂H₂₃N₃O₃F 396.1723 (M+H)⁺, found 396.1739, time 0.53 min; HPLC[Waters XTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrilein 0.1% TFA/water at 1.0 mL/min, 5-95% over 15 min], t_(R)=10.8 min,100% purity.

EXAMPLE 7566-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}pyridazine-3-carboxamidemethanesulfonate

Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example721, Part C) (0.406 g, 1.49 mmol), 3,3-dimethylbutylamine (0.216 mL,1.56 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Addmethanol (7.4 mL), cap and stir overnight. Add NaBH₄ (0.060 g, 1.56mmol) and stir until the gasses stop evolving. Filter the reactionmixture, then concentrate it. Purify by eluting through a 40 g ISCO®column with 6% to 30% (2.0 M NH₃ in methanol) in 80% (ethyl acetate inhexanes) to give the title compound as a free base (0.378 g, 71%).Dissolve the free base (0.357, 0.99 mmol) in methanol (2.5 mL) anddichloromethane (2.5 mL). Add 0.5 M methanesulfonic acid (1.99 mL, 0.99mmol) in dichloromethane. Stir for 10 minutes, then concentrate to givethe title the methane sulfonic acid salt (0.476 g, ˜100%): TOF MS ES⁺359.2 (M+H)⁺, HRMS calcd for C₁₉H₂₇N₄O₃ 359.2083 (M+H)⁺, found 359.2099,time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18], t_(R)=10.7 min, 96.8% purity.

EXAMPLE 7576-(2-Fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamidemethanesulfonate

Place 6-(2-fluoro-4-formylphenoxy)nicotinamide (Example 223, step 1)(0.700 g, 2.69 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.348 g, 2.69mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(13.5 mL), cap and stir overnight. Add NaBH₄ (0.204 g, 5.38 mmol) andstir until the gasses stop evolving. Filter the reaction mixture, thenconcentrate it. Purify by chromatography eluting with 0% to 20% (2.0 MNH₃ in methanol) in ethyl acetate over 1 hour at 20 mL/min to give6-(2-fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide.(0.717 g, 71.3%). Dissolve the compound in dichloromethane: methanol (10mL) and add 1 equivalent of 0.50 M methanesulfonic acid indichloromethane. Stir the solution for a short time before concentratingto give the title compound (0.904 g): TOF MS ES⁺ 374.2 (M+H)⁺, HRMScalcd for C₂₀H₂₅N₃O₃F 374.1880 (M+H)⁺, found 374.1881, time 0.55 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=8.7 min, 100% purity.

EXAMPLE 7585-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}-2-methylphenoxy)pyrazine-2-carboxamide

Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404,part D) (0.600 g, 2.33 mmol), 2-(4-fluorophenyl)ethylamine (0.325 g,2.33 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Addmethanol (11.7 mL), cap and stir overnight. Add NaBH₄ (0.088 g, 2.33mmol) and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 5% to 20% (2.0 M NH₃ in methanol) in ethyl acetate. Concentrate thefraction containing the product, then take it up in EtOAc (100 mL). Washthe organic solution with 1.0 N NaOH (2×25 mL), dry it over Na₂SO₄ andconcentrate it to give the title compound (0.478 g, 54.0%): TOF MS ES⁺381.2 (M+H)⁺, HRMS calcd for C₂₁H₂₂N₄O₂F 381.1727 (M+H)⁺, found381.1729, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18], t_(R)=11.3 min, 97.8% purity.

EXAMPLE 7595-{2-Methyl-4-[(2-pyridin-3-yl-ethylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404,part D) (0.600 g, 2.33 mmol), 2-pyridin-3-ylethylamine (0.285 g, 2.33mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(11.7 mL), cap and stir overnight. Add NaBH₄ (0.088 g, 2.33 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 25% (2.0 M NH₃ in methanol) in ethyl acetate. Concentrate thefraction containing the product, then take it up in EtOAc (100 mL). Washthe organic solution with 1.0 N NaOH (2×25 mL), dry it over Na₂SO₄ andconcentrate it to give the title compound (0.315 g, 37.2%): TOF MS ES⁺364.2 (M+H)⁺, HRMS calcd for C₂₀H₂₂N₅O₂ 364.1773 (M+H)⁺, found 367.1774,time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18], t_(R)=6.1 min, 100% purity.

EXAMPLE 7606-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamidemethanesulfonate

Dissolve6-(4-{[2-(4-fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide(Example 430) (8.40 g, 2.12 mmol) in dichloromethane:methanol (1:1)(4.25 mL) and add 1 equivalent of 0.50 M methanesulfonic acid indichloromethane. Stir the solution for a short time before concentratingto give the title compound (0.1.02 g): TOF MS ES⁺ 396.2 (M+H)⁺, HRMScalcd for C₂₂H₂₃N₃O₃, F 396.1723 (M+H)⁺, found 396.1731, time 0.39 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=10.9 min, 100% purity.

EXAMPLE 7615-(2-Methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamidemethanesulfonate

Place 5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (Ex 391, PartA) (0.600 g, 2.20 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.285 g,2.20 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Addmethanol (11.0 mL), cap and stir overnight. Add NaBH₄ (0.0833 g, 2.20mmol) and stir until the gasses stop evolving. Filter the reactionmixture, then concentrate it. Purify by chromatography eluting with 5%to 30% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes to give5-(2-methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide.(0.6103 g, 71.9%). Dissolve the compound in dichloromethane:methanol(3.2 mL) and add 1 equivalent of 0.50 M methanesulfonic acid indichloromethane. Stir the solution for a short time before concentratingto give the title compound (0.775 g): TOF MS ES⁺ 386.2 (M+H)⁺, HRMScalcd for C₂₁H₂₈N₃O₄ 386.2080 (M+H)⁺, found 386.2078, time 0.39 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=9.3 min, 100% purity.

EXAMPLE 7625-{2-Methoxy-4-[(3-methylbutylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), isoamylamine (0.234 g, 2.69 mmol) and 3{acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), capand stir overnight. Add NaBH₄ (0.0969 g, 2.56 mmol) and stir until thegasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to20% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes.Concentrate the fraction containing the product, and dissolve it inEtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dryit over Na₂SO₄, filter and concentrate to give the title compound (0.484g, 54.9%): TOF MS ES⁺ 345.2 (M+H)⁺, HRMS calcd for C₁₈H₂₅N₄O₃ 345.1927(M+H)⁺, found 345.1938, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=10.1 min, 95.4%purity.

EXAMPLE 7635-{2-Methoxy-4-[(4-methylpentylamino)methyl]phenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 4-methylpentylamine (Example 433, Part A)(0.272 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial.Add methanol (12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g,2.56 mmol) and stir until the gasses stop evolving. Load the reactionmixture directly onto a 25 g ISCO® pre-load column. Dry the column in avacuum oven at room temperature. Purify by eluting through a 40 g ISCO®column with 5% to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45minutes. Concentrate the fraction containing the product, then take itup in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25mL), dry it over Na₂SO₄, filter and concentrate. Dissolve the product inether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and thenconcentrate to about a quarter of the volume. Filter the precipitate togive the title compound (0.335 g, 36.5%): TOF MS ES⁺ 359.2 (M+H)⁺, HRMScalcd for C₁₉H₂₇N₄O₃ 359.2083 (M+H)⁺, found 359.2087, time 0.38 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.3 min, 100% purity.

EXAMPLE 7645-{4-[(3,3-Dimethylbutylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 3,3-dimethylbutylamine (0.272 g, 2.69mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g, 2.56 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes.Concentrate the fraction containing the product, then take it up inEtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dryit over Na₂SO₄, filter and concentrate. Dissolve the product inether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and thenconcentrate to about a quarter of the volume. Filter the precipitate togive the title compound (0.421 g, 45.9%): TOF MS ES⁺ 359.2 (M+H)⁺, HRMScalcd for C₁₉H₂₇N₄O₃ 359.2083 (M+H)⁺. found 359.2093, time 0.38 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.0 min, 98.0% purity.

EXAMPLE 7655-{4-[(4,4-Dimethylpentylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 4,4-dimethylpentylamine (0.310 g, 2.69mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g, 2.56 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes.Concentrate the fraction containing the product, then add EtOAc (100mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it overNa₂SO₄, filter and concentrate. Dissolve the product inether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and thenconcentrate to about a quarter of the volume. Filter the precipitate togive the title compound (0.356 g, 37.3%): TOF MS ES⁺ 373.2 (M+H)⁺, HRMScalcd for C₂₀H₂₉N₄O₃ 373.2240 (M+H)⁺, found 373.2245, time 0.39 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.0 min, 98.7% purity.

EXAMPLE 7665-{4-[(3-Ethylpentylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 3-ethylpentylamine (Example 733, Part B)(0.310 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial.Add methanol (12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g,2.56 mmol) and stir until the gasses stop evolving. Load the reactionmixture directly onto a 25 g ISCO® pre-load column. Dry the column in avacuum oven at room temperature. Purify by eluting through a 40 g ISCO®column with 5% to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45minutes. Concentrate the fraction containing the product, then add EtOAc(100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry itover Na₂SO₄, filter and concentrate. Dissolve the product inether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and thenconcentrate to about a quarter of the volume. Filter the precipitate togive the title compound (0.302 g, 31.7%): TOF MS ES⁺ 373.2 (M+H)⁺, HRMScalcd for C₂₀H₂₉N₄O₃ 373.2240 (M+H)⁺, found 373.2247, time 0.39 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=12.0 min, 100% purity.

EXAMPLE 7675-(4-{[2-(4-Fluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 4-fluorophenethylamine (0.374 g, 2.69mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g, 2.56 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes.Concentrate the fraction containing the product, then add EtOAc (100mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it overNa₂SO₄, filter and concentrate. Dissolve the product inether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and thenconcentrate to about a quarter of the volume. Filter the precipitate togive the title compound (0.545 g, 53.4%): TOF MS ES⁺ 397.2 (M+H)⁺, HRMScalcd for C₂₁H₂₂N₄O₃F 397.1676 (M+H)⁺, found 397.1689, time 0.38 min;HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrilein 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=11.2 min, 100% purity.

EXAMPLE 7685-{4-[(2-Isopropoxyethylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamide

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719,Part A) (0.700 g, 2.56 mmol), 2-isopropoxyethylamine (0.278 g, 2.69mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol(12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g, 2.56 mmol) andstir until the gasses stop evolving. Load the reaction mixture directlyonto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven atroom temperature. Purify by eluting through a 40 g ISCO® column with 5%to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes.Concentrate the fraction containing the product, then take it up inEtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dryit over Na₂SO₄, filter and concentrate to give the title compound (0.512g, 55.5%): TOF MS ES⁺ 361.2 (M+H)⁺, HRMS calcd for C₁₈H₂₅N₄O₄ 361.1876(M+H)⁺, found 361.1891, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=9.4 min, 100% purity.

EXAMPLE 7695-{2-Methoxy-4-[(3-methoxypropylamino)methyl]phenoxy}pyrazine-2-carboxamide

Part A: 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide

Dissolve 5-chloropyrazine-2-carboxamide (Example 387, Part A) (0.374 g,2.34 mmol) and vanillin (0.361 g, 2.34 mmol) in DMF (23.7 mL). Add K₂CO₃(0.821 g, 8.94 mmol) and heat at 100° C. for 1.5 hours. Concentrate thereaction mixture. Take the solid up in water (50 mL) and extract withdichloromethane (3×100 mL). Dry the organic layer over Na₂SO₄, filterand concentrate to give the title compound (0.625 g, 96.4%): TOF MS ES⁺274.1 (M+H)⁺, HRMS calcd for C₁₃H₁₂N₃O₄ 274.0828 (M+H)⁺, found 274.0829,time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1%TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 19 min],t_(R)=10.2 min, 98.1% purity.

-   Part B: Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide    (Part A) (0.700 g, 2.56 mmol), 3-methoxypropylamine (0.240 g, 2.69    mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add    methanol (12.8 mL), cap and stir overnight. Add NaBH₄ (0.0969 g,    2.56 mmol) and stir until the gasses stop evolving. Load the    reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the    column in a vacuum oven at room temperature. Purify by eluting    through a 40 g ISCO® column with 5% to 20% (2.0 M NH₃ in methanol)    in ethyl acetate over 45 minutes. Concentrate the fraction    containing the product, then take it up in EtOAc (100 mL). Wash the    organic solution with 1.0 N NaOH (2×25 mL), dry it over Na₂SO₄    filter and concentrate to give the title compound (0.484 g, 54.6%):    TOF MS ES⁺ 347.2 (M+H)⁺, HRMS calcd for C₁₇H₂₃N₄O₄ 347.1719 (M+H)⁺,    found 347.1729, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm,    S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0    mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=8.0 min, 100%    purity.

EXAMPLE 770 N-Methyl-6-[4-(phenethylamino-methyl)-phenoxy]-nicotinamide

Step 1 Starting from 6-(4-Formyl-phenoxy)-nicotinic acid

Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (1.5 g, 5.53mmol), MeOH (5 mL), THF (5 mL), and 5N NaOH (aq) (2 mL). Reflux thereaction 18 hours and then add 1N HCl (aq) (2 mL). After concentratingthe reaction on the rotovap, add Ethyl acetate to precipitate out thedesired product. Filter and concentrate the ethyl acetate filtrate toafford 1.14 g (85% yield) of the title compound: TLC 1:1 Hexanes:Ethylacetate R_(f):=0.01.

Step 2 6-[4-(Phenethylamino-methyl)-phenoxy]-nicotinic acid ethyl ester

Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (0.62 g, 2.29mmol), MeOH (12 mL), Trimethylorthoformate (8 mL), and Phenethylamine(0.26 mL, 2.06 mmol). After the reaction stirs at room temperature undera Nitrogen atmosphere for 3.5 hours, add NaBH4 (251.0 mg, 2.75 mmol).After the reaction stirs at room temperature for 12 hours, concentrateunder reduced pressure and add the mixture to a 5 g SCX column. Wash thecolumn with MeOH and elute with 1N NH₃ MeOH to afford 854.0 mg (99%yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 2.8 (2H, t),2.8-3.0 (4H, m), 3.8 (2H, s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (9H, m),8.3 (1H, d), 8.8 (1H, s); MS m/z 377 (M+1).

Step 3 [4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamicacid tert-butyl ester

Combine6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinicacid (0.097 g, 0.21 mmol), CH₂Cl₂ (5 mL), EDC (0.048 g, 0.25 mmol), HOBt(0.034 g, 0.25 mmol), Hunig's Base (92 uL, 0.53 mmol), and MethylamineHydrochloride (0.014 g, 0.21 mmol) in a 7 mL reaction vial. Afterreactions shake for 72 hours, add 10% Citric acid, followed by 10%NaHCO₃, and then add the organic mixture to a Celite column. Elute withCH₂Cl₂, concentrate, and flash chromatograph using 2:1 Ethylacetate:Hexanes eluent to afford 55.4 mg (57% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.0(3H, s), 4.2-4.4 (2H, m), 4.3-4.5 (2H, m), 6.3-6.4 (1H, br s), 6.9 (1H,d), 7.0-7.4 (9H, m), 8.1 (1H, d), 8.6 (1H, s); MS m/z 362 (M−100, Boc).

Step 4 N-Methyl-6-[4-(phenethylamino-methyl)-phenoxy]-nicotinamide

Combine [4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamicacid tert-butyl ester (55.4 mg, 0.12 mmol), CH₂Cl₂ (4 mL), and TFA 99%(0.8 mL) in a 7 mL reaction vial. After reaction shakes on shaker atroom temperature for 24 hours, concentrate under reduced pressure. Addthe reaction mixture to a 2 g SCX column, wash with MeOH, and elute with1N NH₃ MeOH. Concentrate sample to afford 41.2 mg (95% yield) of thetitle compound: ¹H NMR (500 MHz, CDCl₃); 1.5 (1H, br m), 2.7-3.0 (7H,m), 3.7 (2H, s), 6.2 (1H, br s), 6.9 (1H, d), 7.0-7.4 (9H, m), 8.0 (1H,d), 8.4 (1H, s); MS m/z 363 (M+1).

EXAMPLES 771-827 Intermediate 16-Methoxy-1,2,3,4-tetrahydro-isoquinoline

Combine 2-(3-Methoxyphenol)ethylamine (10.0 g, 66.13 mmol), 88% Formicacid, and paraformaldehyde (2.05 g, 68.25 mmol) at 0° C. After thereaction stirs at room temperature for 24 hours, concentrate underreduced pressure. Add Acetyl chloride in MeOH (5 ml in 80 ml of MeOH) atroom temperature and stir for 10 minutes. After concentration, trituratethe reaction mixture with ethyl acetate, cool to room temperature, andfilter to afford 8.76 g, 53.7 mmol (81% yield) of the title compound asa white solid:

¹H NMR (500 MHz d-MeOH); 3.05-13.15 (2H, m), 3.45-3.55 (2H, m), 3.70(3H, s), 4.30 (2H, s), 4.8-5.0 (1H, br s), 6.8-6.9 (2H, m), 7.1-7.2 (1H,m); MS m/z 163 (M+).

Intermediate 2 6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline

Combine 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline (5.0, 20.5 mmol) and48% HBr(aq), 20 ml at room temperature. After the reaction refluxes for24 hours, cool the reaction to room temperature and concentrate underreduced pressure. Triturate with ethyl acetate and filter to afford 5.5g, 20.5 mmol (99% yield) of the title compound as a tan solid: ¹H NMR(500 MHz, DMSO); 2.8-2.9 (2H, m), 3.3-3.4 (2H, m), 4.1 (2H, s), 6.5-6.7(2H, m), 6.9-7.1 (1H, m), 8.8-9.0 (2H, br s), 9.4-9.5 (1H, s).

Intermediate 3 6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine 6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline (5.5 g, 23.9 mmol),THF, 100 ml, Et₃N (8.3 ml, 59.8 mmol), and Boc-anhydride (8.3 g, 28.7mmol). After the reaction stirs at room temperature for 72 hours undernitrogen, concentrate under reduced pressure and then flashchromatograph using 1:1 Hexanes:Ethyl acetate eluent to afford 3.51 g,14.1 mmol (59% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃);1.5 (9H, br s), 2.7-2.8 (2H, m), 3.5-3.6 (2H, m), 4.4 (2H, s), 6.5-6.8(2H, m), 6.9-7.0 (1H, m); MS m/z 150 (M+).

Intermediate 46-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine in a round bottom flask equipped with a Dean Stark Trap6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 ml and 30 mlrespectively), K₂CO₃ (1.25 g, 9.04 mmol) and 4-Fluorobenzonitrile (0.72g, 6.04 mmol). Reflux the reaction under a Nitrogen atomosphere for 4hours then cool to room temperature. Add water to the reaction mixtureand extract the product from the water layer using ethyl acetate. Theproduct, a white solid, precipitates out from the ethyl acetate toafford 1.93 g, 5.5 mmol (87% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H,s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (2H m); MS m/z 249 (M+).

Intermediate 56-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine 6-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.93, 5.51 mmol), t-butyl alcohol (50 ml), andKOH (1.56 g, 27.6 mmol). After the reaction stirs for 72 hours at roomtemperature, concentrate under reduced pressure then add ethyl acetate.Wash the ethyl acetate with a brine solution and dry the organic layerover Na₂SO₄. After concentrating the organic layer under reducedpressure, the reaction affords 1.93 g, 2.50 mmol (95% yield) of thetitle compound as a white solid:

¹H NMR (500 MHz, CDCl₃); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H,m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m),7.7-7.9 (2H, m); TLC R_(f)=0.5 2:1 Hexanes:Ethyl acetate.

Intermediate 6 4-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-benzamide

Combine 6-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 10.83 mmol), CH₂Cl₂ (100 ml), and TFA (25ml) at room temperature. After the reaction stirred for 24 hoursfollowed by the addition of 1M K₂CO₃ (aq), extract the product out ofthe aqueous layer with several washings of ethyl acetate/THF.Concentrate the organic phase under reduced pressure and add to 2, 10 gSCX Columns pre-treated with 5% AcOH/MeOH. After several washings of theSCX Columns with MeOH, the elute the product using 1N NH₃-MeOH solutionto afford 2.08 g, 7.7 mmol (71% yield) of the title compound as a whitefoam: ¹H NMR (500 MHz, DMSO); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m),3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m),7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m),9.2-9.4 (2H, m); MS m/z 269 (M+1).

EXAMPLE 7714-(2-Pentyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Combine 4-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-benzamide (80.0 mg,0.30 mmol), DMF (4 mL), Et₃N (0.2 mL, 1.32 mmol), and Pentylbromide (0.1mL, 0.66 mmol) in a 7 mL vial. Place vial on shaker at 70° C. for 72hours and then added Ethyl acetate to reaction vial, wash with water andseveral times with 10% LiCl(aq), dry over Na₂SO₄. Concentrate theorganic mixture and flash chromatograph using 2% 1N NH₃ MeOH, 20% THF,78% CH₂Cl₂ to afford 78.0 mg (77% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 0.9-1.0 (3H, m), 1.3-1.4 (4H, m), 1.5-1.7 (2H, m),2.4-2.6 (2H, m), 2.7-2.8 (2H, m), 2.8-3.0 (2H, m), 3.5-3.6 (2H, m),6.8-6.8 (2H, m), 6.9-7.1 (3H, m), 7.7-7.9 (2H, m); MS m/z 339 (M+1).

EXAMPLE 7724-[2-(3-Methyl-butyl)-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-benzamide

Using a method similar to Example 771, using Isoamylbromide (0.1 mL,0.66 mmol) gives 63.0 mg (62% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 0.9-1.0 (6H, m), 1.4-1.8 (3H, m), 2.5-2.6 (2H, m), 2.7-2.8(2H, m), 2.9-3.0 (2H, m), 3.6-3.8 (2H, m), 6.8-7.1 (5H, m), 7.7-7.9 (2H,m); MS m/z 339 (M+1).

EXAMPLE 7734-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Using a method similar to Example 771, using Benzylbromide (0.1 mL, 0.66mmol) gives 81.0 mg (75% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 2.6-2.8 (2H, m), 2.8-3.0 (2H, m), 3.5-3.7 (4H, m), 5.6-6.1 (2H,br s), 6.7-6.8 (2H, m), 6.8-7.0 (3H, m), 7.2-7.4 (5H, m), 7.7-7.9 (2H,m); MS m/z 359 (M+1).

EXAMPLE 7744-(5-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide

Using a method similar to Example 771, using Phenethylbromide (0.1 mL,0.66 mmol) gives 81.9 mg (73% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 2.7-3.0 (7H, m), 3.6-3.8 (3H, m), 5.8-6.2 (2H, br s),6.8-7.1 (5H, m), 7.2-7.4 (5H, m), 7.7-7.9 (2H, m); MS m/z 373 (M+1).

Intermediate 76-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine in a round bottom flask equipped with a Dean Stark Trap6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(5.42 g, 21.74 mmol), Toluene, Dimethylacetamide (30 ml and 90 mlrespectively), K₂CO₃ (4.51 g, 32.61 mmol), and 6-Chloronicatinamide(3.40, 21.74 mmol). Reflux the reaction under a Nitrogen atomosphere for4 hours then cool to room temperature. Add water to the reaction mixtureand extract the product from the water layer using ethyl acetate. Theproduct, a white solid, precipitates out from the ethyl acetate toafford 5.8 g, 15.7 mmol (72% yield) of the title compound: ¹H NMR (500MHz, DMSO); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.5-3.6 (2H, m), 4.4-4.6 (2H,m), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.5 (1H, s), 8.1(1H, s), 8.2-8.3 (1H, m), 8.6 (1H, m).

Intermediate 8 6-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-nicotinamide

Combine6-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 10.83 mmol), CH₂Cl₂ (100 mL), and TFA (25mL). After reaction stirs at room temperature for 12 hours, add 1M K₂CO₃and CHCl₃ to the reaction. Separate the organic layer, wash with brine,and dry over Na₂SO₄. Concentrate under reduced pressure and add mixtureto 2, 10 g SCX columns, wash with MeOH, and elute with 1N NH₃ MeOH.Concentrate to afford 2.91 g, 10.8 mmol (71% yield) of the titlecompound as a white foam: ¹H NMR (500 MHz, DMSO); 2.9-3.1 (2H, m),3.2-3.5 (2H, m), 4.2-4.4 (2H, m), 6.9-7.2 (3H, m), 7.2-7.4 (1H, m),7.4-7.6 (1H, m), 7.9-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.7 (1H, m),8.2-9.4 (2H, m); MS m/z 269 (M+1).

EXAMPLE 7756-(2-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-nicotinamideNF7-AOO855-011

Combine 6-(1,2,3,4-Tetrahydro-isoquinolin-6-yloxy)-nicotinamide (46.9mg, 0.17 mmol), DMF (3 mL), Et₃N (0.1 mL, 0.77 mmol), andPhenethylbromide (52 uL, 0.38 mmol) in a 7 mL vial. Add reaction vial toa shaker at 70° C. for 72 hours, and then add water and Ethyl acetate.Extract the Ethyl acetate several times with water, 10% LiCl, and dryover Na₂SO₄. Concentrate organic mixture and flash chromatograph using30% THF, 4% 1N NH₃ MeOH, 76% CH₂Cl₂ to afford 23.2 mg, (37% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 1.1-1.2 (1H, m), 1.6-2.1(7H, m), 2.6-3.0 (9H, m), 3.6-4.0 (6H, m), 5.7-5.8 (1H, m), 6.8-7.3 (9Hm), 8.0-8.2 (1H, m), 8.5-8.6 (1H, m); MS m/z 374 (M+1).

By the method of example 775 the following compounds were prepared,isolated as the free base:

Name of the Final No.: X′ Compound Data 776 Benzyl 6-(2-Benzyl-1,2,3,4-Mass spectrum (ion tetrahydro-isoquinoline- spray): m/z = 360 (M + 1);6-yloxy)-nicotinamide ¹H NMR (500 MHz, (CDCl₃) 2.7-3.0(4H, m), 3.6-3.8(4H, m), 6.8-7.1(3H, m), 7.2-7.5(4H, m), 8.1-8.2(1H, m), 8.5-8.7(1H, s).777 Penty] 6-(2-Pentyl-1,2,3,4- Mass spectrum (ion spray):tetrahydro-isoquinolin- m/z = 340 (M + 1); 6-yloxy)-nicotinamide ¹H NMR(500 MHz, (CDCl₃) 0.8-1.0(3H, m), 1.2-1.4 (4H, m), 1.5-1.7(2H, m),2.4-2.6(2H, m), 2.7- 2.8(2H, m), 2.8-3.0 (2H, m), 3.6-3.7(2H, m),5.8-6.3(1H, br d), 6.8-7.1(4H, m), 8.1-8.2 (1H, m), 8.5-8.7(1H, s). 7782-1H-Indo-3-yl-ethyl 6-[2-(3-Phenyl-propyl)- Mass spectrum (ion1,2,3,4-tetrahydro- spray): m/z = 413 (M + 1); isoquinolin-6-yloxy]-nicotmamide 779 2-(3-Chloro-benzyl) 6-[2-(3-Chloro-benzyl)- Massspectrum (ion 1,2,3,4-tetrahydro- spray): m/z = 388 (M + 1);isoquinoline-6-yloxy]- nicotmamide 780 2-(2-Carbamoyl-ethyl)6-[2-(2-Carbamoyl- Mass spectrum (ion ethyl)-1,2,3,4- spray): m/z = 341(M + 1); tetrahydro-isoquinolin- 6-yloxy]-nicotinamide 7812-(2-Phenylsulfanyl- 6-[2-(2-Phenylsulfanyl- Mass spectrum (ion ethyl)ethyl)-1,2,3,4- spray): m/z = 406 tetrahydro-isoquinolin- (M + 1);6-yloxy]-nicotinamide 782 2-(3-Methyl-butyl) 6-[2-(3-Methyl-butyl)- Massspectrum (ion 1,2,3,4-tetrahydro- spray): m/z = 340 (M + 1);isoquinolin-6-yloxy]- nicotinamide 783 2-(4-Trifluoromethyl-6-[2-(4-Trifluoromethyl- Mass spectrum (ion benzyl) benzyl)-1,2,3,4-spray): m/z = 428 (M + 1); tetrahydro-isoquinolin- 6-yloxy]-nicotinamide784 2-(3-Chloro-benzyl) 6-[2-(3-Chloro-benzyl)- Mass spectrum (ion1,2,3,4-tetrahydro- spray): m/z = 394 (M + 1); isoquinolin-6-yloxy]-nicotinamide 785 2-(3-Phenyl-allyl) 6-[2-(3-Phenyl-allyl)- Mass spectrum(ion 1,2,3,4-tetrahydro- spray): m/z = 386 (M + 1);isoquinolin-6-yloxy]- nicotinamide 786 Benzo[b]thiopheny- 6-(2- Massspectrum (ion 3-ylmethy[ Benzo[b]thiopheny-3- spray): m/z = 450 (M + 1);ylmethyl-1,2,3,4- tetrahydro-isoquinolin- 6-yloxy)-nicotinamide 7872-Cyclopropylmethyl 6-(2-Cyclopropylmethyl Mass spectrum (ion1,2,3,4-tetrahydro- spray): m/z = 324 (M + 1); isoquinolin-6-yloxy)-nicotinamide 788 2-(3,5-Bis- 6-[2-(3,5-Bis- Mass spectrum (iontrifluoromethyl-benzyl) trifluoromethyl-benzyl)- spray): m/z = 496 (M +1); 1,2,3,4-tetrahydro- isoquinolin-6-yloxy]- nicotinamide 7892-(3-Bromo-benzyl) 6-[2-(Bromo-benzyl)- Mass spectrum (ion1,2,3,4-tetrahydro- spray): m/z = 438 (M); isoquinolin-6-yloxy]-nicotinamide 790 2-(4-Methyl-benzyl) 6-[2-(4-Methyl-benzyl)- Massspectrum (ion 1,2,3,4-tetrahydro- spray): m/z = 374 (M + 1);isoquinolin-6-yloxy]- nicotinamide 791 2-(2-Fluoro-benzyl)6-[2-(2-Fluoro-benzyl)- Mass spectrum (ion 1,2,3,4-tetrahydro- spray):m/z = 378 (M + 1); isoquinolin-6-yloxy]- nicotinamide 7922-(3-Methoxy-benzyl) 6-[2-(3-Methoxy- Mass spectrum (ionbenzyl)-1,2,3,4- spray): m/z = 390 tetrahydro-isoquinolin- (M + 1);6-yloxy]-nicotinamide 793 2-(1H-Benzoimidazol- 6-[2-(1H- Mass spectrum(ion 2-ylmethyl) Benzoimidazol-2- spray): m/z = 400 (M + 1);ylmethyl)-1,2,3,4- tetrahydro-isoquinolin- 6-yloxy]-nicotinamide 7942-(5-Chloro-thiophen- 6-[2-(5-Chloro-thophen- Mass spectrum (ion2-ylmethyl) 2-ylmethyl)-1,2,3,4- spray): m/z = 400tetrahydro-isoquinolin- (M + 1); 6-ylozy]-nicotinamide 7952-(2,6-Dichloro-benzyl) 6-[2-(2,6-Dichloro- Mass spectrum (ionbenzyl)-1,2,3,4- spray): m/z = 428 (M); tetrahydro-isoquinolin-6-yloxy]-nicotinamide 796 2-(3-Fluoro-benzyl) 6-[2-(3-Fluoro-benzyl)-Mass spectrum (ion 1,2,3,4-tetrahydro- spray): m/z = 378isoquinolin-6-yloxy]- (M + 1); nicotinamide 797 2-[2-(4-Methoxy-6-{2-[2-(4-Methoxy- Mass spectrum (ion phenyl)-ethyl]phenyl)-ethyl]-1,2,3,4- spray): m/z = 404 tetrahydro-isoquinolin- (M +1); 6-yloxy}-nicotinamide 798 3-Propionic acid 3-[6-(5-Carbamoy]- Massspectrum (ion pyridin-2-yloxy)-3,4- spray): m/z = 342dihydro-1H-isoquinolin- (M + 1); 2yl]-propionic acid 7992-(3-Piperidin-1-yl-propyl) 6-[2-(3-Piperidin-1-yl- Mass spectrum (ionpropyl)-1,2,3,4- spray): m/z = 395 tetrahydro-isoquinolin- (M + 1);6-yloxy]-nicotinamide 800 2-Pent-4-ynyl 6-(2-Pent-4-ynyl- Mass spectrum(ion 1,2,3,4-tetrahydro- spray): m/z = 336 isoquinolin-6-yloxy)- (M +1); nicotinamide 801 2-(2-Piperidin-1-yl-ethyl) 6-[2-(2-Piperidin-1-yl-Mass spectrum (ion ethyl)-1,2,3,4- spray): m/z = 381tetrahydro-isoquinolin- (M + 1); 6-yloxy]-nicotinamide 8022-(2-Diisopropylamino- 6-[2-(2- Mass spectrum (ion ethyl)Diisopropylamino- spray): m/z = 397 ethyl)-1,2,3,4- (M + 1);tetrahydro-isoquinolin- 6-yloxy]-nicotinamide 8032-(3,3,4,4-Tetrafluoro- 6-[2-(3,3,4,4- Mass spectrum (ion butyl)Tetrafluoro-butyl)- spray): m/z = 398 1,2,3,4-tetrahydro- (M + 1);isoquinolin-6-yloxy]- nicotinamide 804 2-Cyclobutylmethyl6-(2-Cyclobutylmethyl- Mass spectrum (ion 1,2,3,4-tetrahydro- spray):m/z = 338 isoquinolin-6-yloxy)- (M + 1); nicotinamide 8052-(3,3-Dimethyl-butyl) 6-[2-(3,3-Dimethyl- Mass spectrum (ionbutyl)-1,2,3,4- spray): m/z = 354 tetrahydro-isoquinolin- (M + 1);6-yloxy]-nicotinamide 806 2-(3,4,4-Trifluoro- 6-[2-(3,4,4-Trifluoro-Mass spectrum (ion but-3-enyl) but-3-enyl)-1,2,3,4- spray): m/z = 378tetrahydro-isoquinolin- (M + 1); 6-yloxy]-nicotinamide 8072-(2-Methoxy-benzyl) 6-[2-(2-Methoxy- Mass spectrum (ionbenzyl)-1,2,3,4- spray): m/z = 390 tetrahydroisoquinolin-6- (M + 1);yloxy]-nicotinamide 808 2-Pyridin-3-ylmethyl 6-(2-Pyridin-3- Massspectrum (ion ylmethyl-1,2,3,4- spray): m/z = 361tetrahydro-isoquinolin- (M + 1); 6-yloxy)-nicotinamide

Intermediate 9 [2-(3-Methoxy-phenyl)-ethyl]-carbamic acid methyl ester

Combine Methoxyphenylethylamine (9.6 ml, 66.1 mmol), THF (300 ml), Et₃N(11.0 ml, 78.9 mmol), and methyl chloroformate (26.0 ml, 339 mmol) at 0°C. under nitrogen atmosphere. After the reaction stirs at roomtemperature for 18 hours, add the mixture into water, wash with brine,and dry the organic layer over Na₂SO₄ followed by concentrating underreduced pressure. Flash chromatograph using 2:1 Hexanes:Ethyl acetate toafford 13.6 g, 65.0 mmol (98% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 2.8 (2H, t, J=6.7, 7.0 Hz), 3.41-3.46 (2H, m), 3.7 (3H, s),3.8 (3H, s), 4.6-4.8 (1H, b s), 6.7-6.8 (3H, m), 7.2-7.3 (1H, m); MS m/z210 (M+1).

Intermediate 10 8-Methoxy-3,4-dihydro-2H-isoquinolin-1-one

Combine polyphosphoric acid (30 g) at 180° C. and[2-(3-Methoxy-phenyl)-ethyl]-carbamic acid methyl ester (3.0 g, 14.33mmol). After the reaction stirs for 15 minutes then add to a beaker ofice. Extract the product from the water using CH₂Cl₂ and CHCl₃. Dry theorganic layer over Na₂SO₄ and then concentrate under reduced pressure.Flash chromatograph using 5% MeOH in Ethyl acetate to afford 0.340 g,1.92 mmol (13% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃);2.92 (2H, t, J=6.4), 3.43-3.47 (2H, m), 3.85 (3H, s), 6.2-6.3 (1H, b s),6.8-6.9 (2H, m), 7.3-7.4 (1H, m), 7.5-7.6 (2H, m); MS m/z 178 (M+1).

Intermediate 11 8-Methoxy-1,2,3,4-tetrahydro-isoquinoline

Combine 8-Methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.778 g, 4.40 mmol),THF (20 ml), and LiAlH₄ (0.333 g, 8.8 mmol) at 0° C. under nitrogenatmosphere. After 30 minutes the reaction, reflux for 2 hours and thencool to room temperature. Quench the reaction by adding water and 1MNaOH at 0° C. and stirring for 12 hours at room temperature. Filter thereaction through celite and elute with THF. After concentrating thefiltrate under reduced pressure, add the mixture to a 10 g SCX columnpre-treated with 5% AcOH/MeOH. After rinsing several times with MeOH,elute the product using 1N NH₃-MeOH followed by concentration underreduced pressure to afford 0.665 g, 4.07 mmol (93% yield) of the titlecompound as a tan oil: ¹H NMR (500 MHz, CDCl₃); 1.7-2.0 (1H, b s), 2.77(2H, t, J=5.86), 3.09 (2H, t, J=5.86), 3.8 (3H, s), 3.95 (2H, s),6.6-6.8 (2H, m), 7.0-7.15 (1H, m); TLC 5% MeOH:Ethyl acetate R_(f):=0.1.

Intermediate 12 1,2,3,4-Tetrahydro-isoquinolin-8-ol

Combine 8-Methoxy-tetrahydroisoquinoline (665.7 mg, 4.08 mmol) and 48%HBr at room temperature. Reflux the reaction for 3 hours and then coolto room temperature. Recrystallize the product from EtOH and Diethylether to afford 754.2 mg, 3.28 mmol (80% yield) of the title compound asa tannish white solid: ¹H NMR (500 MHz, DMSO); 2.9 (2H, t, J=6.16,5.86), 3.2-3.4 (2H, m), 4.0 (2H, s), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m),8.8-9.1 (2H, b m), 9.9 (1H, s); MS m/z 148 (M+).

Intermediate 13 8-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

Combine 8-Hydroxy tetrahydroisoquinoline HBr salt (754.2 mg, 3.28 mmol),and Et₃N (2.8 ml, 19.68 mmol), THF anhydrous (20 ml), and Boc-anhydride(1.14 g, 3.94 mmol). Stir the reaction at room temperature for 72 hoursfollowed by an aqueous work-up. Wash the organic layer with brine anddry over Na₂SO₄. After concentrating the organic layer under reducedpressure, flash chromatograph using 4:1 Hexanes:Ethyl acetate eluent toafford 249.6 mg, 1.01 mmol (31% yield) of the title compound as a whitefoam: 1H NMR (500 MHz, CDCl₃); 1.5 (9H, s), 2.73-2.79 (2H, m), 3.5-3.6(2H, m), 4.45-4.61 (2H, b s), 6.6-6.9 (2H, m), 6.9-7.2 (1H, m); TLC 4:1Hexanes:Ethyl acetate R_(f):=0.13

Intermediate 148-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Combine in a 100 ml round bottom flask equipped with stir bar, DeanStark trap, and reflux condenser8-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(249.6 mg, 1.01 mmol), dimethylacetamide (30 ml), toluene (10 ml), K₂CO₃(814.74 mg, 5.90 mmol), and 6-Chloronicatinamide (626.28 mg, 4.0 mmol).Reflux the reaction under nitrogen for 5 hours. After cooling to roomtemperature, add water to the reaction mixture and extract the productusing ethyl acetate. Wash the organic layer with brine and dry overNa₂SO₄. After concentrating under reduced pressure, flash chromatographusing 20% THF in CH₂Cl₂ to afford 245.1 mg, 0.66 mmol (66% yield) of thetitle compound: ¹H NMR (500 MHz, d-MeOH); 1.3-1.5 (9H, m), 2.8-2.9 (2H,m), 3.5-3.7 (2H, m), 3.85 (2H, s), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m),7.2-7.3 (1H, m), 7.5-7.6 (1H, m), 8.2-8.3 (1H, m), 8.6-8.7 (1H, b s),8.8 (1H, s); MS m/z 370 (M+1).

Intermediate 15 6-(1,2,3,4-Tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Combine8-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (249.6 mg, 1.01 mmol), CH₂Cl₂ (25 ml), and TFA (10ml) at room temperature under nitrogen atmosphere. After the reactionstirs for 12 hours then concentrate under reduced pressure. Solubolizethe mixture in MeOH and add to a 2 g SCX Column (pre-treated with 5%AcOH-MeOH), wash several times with MeOH, and elute the product with 1NNH₃MeOH to afford 156.1 mg, 0.58 mmol (57% yield) of the title compound.

EXAMPLE 8096-(2-Phenethyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 786, using Phenethylbromide (40 uL,0.28 mmol) gives 26.9 mg (55% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.8-2.1 (4H, m), 2.7-3.0 (6H, m), 5.9-6.3 (2H, br d),6.8-7.4 (10H, m), 8.1-8.3 (1H, m), 8.5 (1H, s); MS m/z 374 (M+1).

EXAMPLE 8106-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 786, using Benzylbromide (0.1 mL, 0.97mmol) gives 45.6 mg (63% yield) of the title compound.

EXAMPLE 8116-(2-Pentyl-1,2,3,4-tetrahydro-isoquinolin-8-yloxy)-nicotinamide

Using a method similar to Example 786, using Pentylbromide (54 uL, 0.48mmol) gives 32.5 mg (48% yield) of the title compound: ¹H NMR (500 MHz,d-MeOH); 0.8 (3H, t), 1.2-1.3 (4H, m), 1.4-1.6 (2H, m), 2.3-2.5 (2H, m),2.7 (2H, t), 2.9-3.0 (2H, m), 3.5 (2H, s), 6.8-7.2 (5H, m), 8.1-8.2 (1H,m), 8.6 (1H, s); MS m/z 340 (M+1).

Intermediate 16 1,2-Bis-bromomethyl-4-methoxy-benzene

Combine 3,4-Dimethylanisole (2.72 g, 20.0 mmol), CCl₄ (50 mL), NBS (7.12g, 40.0 mmol), and Benzoyl peroxide (40.0 mg, 0.17 mmol). Reflux thereaction for 12 hours and then cool to room temperature and concentrateunder reduced pressure. Flash chromatograph using 4:1 CHCl₃:Hexaneseluent to afford 1.90 g, 6.4 mmol (32% yield) of the title compound: ¹HNMR (500 MHz, CDCl₃); 3.8 (3H, s), 4.6 (2H, s), 4.7 (2H, s), 6.8-6.9(2H, m), 7.1-7.4 (1H, m); TLC 4:1 CHCl₃:Hexanes R_(f):=0.67

Intermediate 17 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindol

Combine in a round bottom flask 1,2-Bis-bromomethyl-4-methoxy-benzene(1.0 g, 3.40 mmol), Benzyltriethylammonium chloride (73.5 mg, 3.2 mmol),50% NaOH (aq)/Toluene (3.0 mL/14 mL), and then dropwise addition ofBenzylamine (0.37 mL, 3.39 mmol). Stir the reaction at room temperaturefor 3 hours, and then add to Ethyl acetate, wash with water, brine, anddry over Na₂SO₄. After concentrating under reduced pressure, the add themixture to a 10 g SCX column, wash with MeOH, and elute with 1NNH₃-MeOH. Flash chromatograph using 3:1 Hexanes:Ethyl acetate to afford580.0 mg, 2.42 mmol (71% yield) of the title compound as a brown oil: ¹HNMR (500 MHz, CDCl₃); 3.7 (3H, s), 3.9-4.0 (6H, m), 6.7-6.8 (2H, m), 7.1(1H, d), 7.3-7.5 (5H, m); MS m/z 238 (M).

Intermediate 18 2-Benzyl-2,3-dihydro-1H-isoindol-5-ol

Combine 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindol (580.0 mg, 2.42 mmol)and 48% HBr (aq) (20 mL). Reflux the reaction for 5 hours and then coolto room temperature. Concentrate the reaction mixture under reducedpressure then add to 5 g a SCX column. Wash the column with MeOH andelute with 1N NH₃-MeOH to afford 265.4 mg, 1.17 mmol (49% yield) of thetitle compound as a brown solid: 1H NMR (500 MHz, d-Methanol); 3.8-3.9(4H, m), 3.91 (2H, s), 6.6-6.7 (2H, m), 7.0 (1H, d), 7.2-7.5 (4H, m); MSm/z 226 (M+1).

EXAMPLE 812 6-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide 0

Combine in a round bottom flask equipped with stir, a Dean Stark Trap,and a nitrogen atmosphere 2-Benzyl-2,3-dihydro-1H-isoindol-5-ol (265.4mg, 1.18 mmol), Toluene (10 mL), DMA (30 mL), K₂CO₃ (244.6 mg, 1.77mmol), and 6-Chloronicatinamide (184.4 mg, 1.18 mmol). Reflux thereaction for 6 hours and then cool to room temperature and add ethylacetate. Wash the Ethyl acetate layer several times with water, brine,and dry over Na₂SO₄. After concentrating under reduced pressure, Purifythe mixture by reverse phase chromatography (5% to 95% 0.01% TFA bufferin acetonitrile/water) to afford 333.4 mg, 0.97 mmol (82% yield) of thetitle compound as a white foam: ¹H NMR (500 MHz, d-Methanol); 4.6-4.8(6H, m), 7.0 (1H, d), 7.1-7.2 (2H, m), 7.4-7.6 (5H, m), 8.2 (1H, d), 8.6(1H, s); MS m/z 346 (M+1).

Intermediate 19 6-(2,3-Dihydro-1H-isoindol-5-yloxy)-nicotinamide

Combine 6-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0mg, 0.67 mmol), EtOH (5 mL), 10% Pd—C (45.0 mg), and a Hydrogen balloon.Stir the reaction at room temperature for 168 hours at atmosphericpressure. Filter the reaction mixture through a pad of Celite using MeOHeluent and then concentrate the filtrate under reduced pressure. Add themixture to a 2 g SCX column, wash with MeOH, and elute using 1NNH₃-MeOH. After concentrating under reduced pressure, purify the mixtureby flash chromatography using 10% 1N NH₃-MeOH/DCM eluent to afford 19.2mg, 0.08 mmol (11% yield) of the title compound as a white solid: ¹H NMR(500 MHz, d-Methanol); 4.1-4.3 (4H, br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H,m), 8.2-8.3 (1H, m), 8.6 (1H, s); MS m/z 254 (M).

EXAMPLE 813 6-(2-Phenethyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide

Combine 6-(2,3-Dihydro-1H-isoindol-5-yloxy)-nicotinamide (19.2 mg, 0.08mmol), DMF (3 mL), Et₃N (46 uL, 0.33 mmol), and 2-Phenethylbromide (23uL, 0.165 mmol). Place the reaction on a shaker for 12 hours at 70° C.,then cool to room temperature and concentrate under reduced pressure.Add the mixture to a 2 g SCX column, wash with MeOH, and then elute with1N NH₃-MeOH. After concentrating the mixture, purify using reverse phasechromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) toafford 9.5 mg, 0.03 mmol (33% yield) of the title compound: ¹H NMR (500MHz, d-Methanol); 2.8-3.2 (4H, m), 4.1-4.2 (4H, m), 6.8-7.1 (3H, m),7.2-7.4 (6H, m), 8.2 (1H, d), 8.6 (1H, s); MS m/z 358 (M).

Intermediate 20 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester

Combine in a round bottom flask equipped with a stir, Dean Stark Trapfilled with toluene, and reflux condenser 4-Hydroxybenzaldehyde (2.14 g,17.5 mmol), K₂CO₃ (3.63 g, 26.3 mmol), 6-Chloronicatinamide (3.25 g,17.5 mmol) and a solution of DMA:Toluene (45:15 mL). After the reactionrefluxes under nitrogen atmosphere for 3 hours, concentrate underreduced pressure and then add ethyl acetate. Wash the organic layerseveral times with water, then brine, and dry over Na₂SO₄. Afterconcentrating under reduced pressure, flash chromatograph using 33%Hexanes, 63% Ethyl acetate eluent to afford 4.70 g, 17.4 mmol (99%yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 1.4 (3H, t),4.3-4.4 (2H, m), 7.1 (1H, d), 7.3-7.4 (2H, m), 7.9-8.0 (2H, m), 8.3 (1H,d), 9.9 (1H, s); TLC 2:1 Hexanes:Ethyl acetate R_(f):=0.55.

Intermediate 21 6-(4-Formyl-phenoxy)-nicotinic acid

Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (1.5 g, 5.53mmol), MeOH (5 mL), THF (5 mL), and 5N NaOH (aq) (2 mL). Reflux thereaction 18 hours and then add 1N HCl (aq) (2 mL). After concentratingthe reaction on the rotovap, add Ethyl acetate to precipitate out thedesired product. Filter and concentrate the ethyl acetate filtrate toafford 1.14 g (85% yield) of the title compound: TLC 1:1 Hexanes:Ethylacetate R_(f):=0.01.

Intermediate 224-[5-(Piperidine-1-carbonyl)-pyridin-2-yloxy]-benzaldehyde

Combine 6-(4-Formyl-phenoxy)-nicotinic acid (250.0 mg, 1.03 mmol), EDC(237.0 mg, 1.23 mmol), HOBt (166.2 mg, 1.23 mmol), and Piperidine (0.10mL, 1.03 mmol) in CH₂Cl₂ (6 mL). After reaction stirs at roomtemperature under a Nitrogen atmosphere for 24 hours, concentrate thereaction mixture using a rotovap, add Ethyl acetate and wash with 0.1NHCl, 10% NaHCO₃, Brine, and dry over Na₂SO₄. After concentrating thereaction mixture, flash chromatograph using 2:1 Ethyl acetate:Hexanes toafford 144.1 mg (45% yield) of the title compound as a white foam: ¹HNMR (500 MHz, CDCl₃); 1.5-1.8 (6H, m), 3.3-3.8 (4H, m), 7.0-7.1 (1H, m),7.3-7.4 (2H, m), 7.8-8.0 (3H, m), 8.3 (1H, m), 9.9 (1H, s); MS m/z 311(M+1).

EXAMPLE 814{6-[4-(Phenethylamino-methyl)-phenoxy]-pyridin-3-yl}-piperidin-1-yl-methanone

Combine 4-[5-(Piperidine-1-carbonyl)-pyridin-2-yloxy]-benzaldehyde (72.0mg, 0.23 mmol), MeOH (2.3 mL), Trimethylorthoformate (1.6 mL), andPhenethylamine (26 uL, 0.21 mmol). After the reaction stirs for 72 hoursat room temperature under a Nitrogen atmosphere, add NaBH₄ (10.5 mg,0.28 mmol). After 5 hours, concentrate the reaction under reducedpressure and add the mixture to a 2 g SCX column. Wash with MeOH andthen 1N NH₃MeOH to afford 72.2 mg (75% yield) of the title compound: ¹HNMR (500 MHz, CDCl₃); 1.5-1.8 (6H, m), 2.8-3.0 (4H, m), 3.3-3.8 (4H, m),3.85 (2H, s), 6.8 (1H, d), 7.1-7.4 (9H, m), 8.0 (1H, d), 8.2 (1H, s); MSm/z 416 (M+1).

EXAMPLE 815(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-piperidin-1-yl-methanone

Using a method similar to Example 814, using Isoamylamine (25 uL, 0.21mmol) gives 63.7 mg (72% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 0.9-1.0 (6H, m), 1.3-1.4 (3H, m), 1.4-1.8 (8H, br m), 2.6 (2H,t), 3.3-3.8 (4H, br m), 3.85 (2H, s), 6.8 (1H, d), 7.1 (2H, d), 7.4 (2H,d), 7.8 (1H, d), 8.2 (1H, s); MS m/z 382 (M+1).

Intermediate 23 6-[4-(Phenethylamino-methyl)-phenoxy]-nicotinic acidethyl ester

Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (0.62 g, 2.29mmol), MeOH (12 mL), Trimethylorthoformate (8 mL), and Phenethylamine(0.26 mL, 2.06 mmol). After the reaction stirs at room temperature undera Nitrogen atmosphere for 3.5 hours, add NaBH4 (251.0 mg, 2.75 mmol).After the reaction stirs at room temperature for 12 hours, concentrateunder reduced pressure and add the mixture to a 5 g SCX column. Wash thecolumn with MeOH and elute with 1N NH₃ MeOH to afford 854.0 mg (99%yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 2.8 (2H, t),2.8-3.0 (4H, m), 3.8 (2H, s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (9H, m),8.3 (1H, d), 8.8 (1H, s); MS m/z 377 (M+1).

Intermediate 24 6-{4-[3-Methyl-butylamino)-methyl]-phenoxy}-nicotinicacid ethyl ester

Using a method similar to Intermediate 23, using Isoamylamine (0.20 ml,0.50 mmol) gives 854.0 mg (99% yield) of the title compound: ¹H NMR (500MHz; CDCl₃); 0.8-0.9 (6H, t), 1.4-1.7 (3H, m), 2.8-3.0 (2H, m), 3.8 (2H,s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (4H, m), 8.3 (1H, d), 8.8 (1H, s);MS m/z 343 (M+1).

Intermediate 256-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinicacid ethyl ester

Combine 6-[4-(Phenethylamino-methyl)-phenoxy]-nicotinic acid ethyl ester(0.854 g, 2.27 mmol), THF (50 mL), Triethylamine (0.8 mL, 5.68 mmol),and Boc-anhydride (0.788 g, 2.72 mmol). After the reaction stirs at roomtemperature under a Nitrogen atmosphere for 2.5 hours, concentrate underreduced pressure. Add Ethyl acetate and wash with sat NH₄Cl (aq), brine,and then dry over Na2SO4. Concentrate the organic mixture under reducedpressure and then flash chromatograph using 8:1 to 3:1 Hexanes:Ethylacetate gradient to afford 333.0 mg (33% yield) of title compound: ¹HNMR (500 MHz, CDCl₃); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.3-3.5 (2H, m), 3.9(3H, s), 4.3-4.4 (2H, m), 6.9 (1H, d), 7.1-7.4 (9H, m), 8.3 (1H, d), 8.8(1H, s); MS m/z 363 (M−100, Boc).

Intermediate 266-(4-{tert-Butoxycarbonyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinicacid ethyl ester

Using a method similar to Intermediate 25, using6-{4-[3-Methyl-butylamino)-methyl]-phenoxy}-nicotinic acid ethyl ester(0.854 g, 2.27 mmol) gives 311.0 mg (31% yield) of the title compound:¹H NMR (500 MHz, CDCl₃); 0.8-0.9 (6H, m), 1.3-1.6 (12H, m), 3.0-3.3 (2H,m), 3.8 (3H, s), 4.2-4.4 (2H, m), 6.9 (1H, d), 7.0-7.3 (5H, m), 8.2 (1H,d), 8.7 (1H, s); TLC 3:1 Hexanes:Ethyl acetate R_(f)=0.34.

Intermediate 276-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinicacid

Combine6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinicacid ethyl ester (0.333 g, 0.72 mmol), MeOH (5 mL), THF (5 mL), and 2.5NNaOH (aq) (2 mL). After the reaction refluxes under a Nitrogenatmosphere for 24 hours, concentrate under reduced pressure. Add 2.5NHCl (aq) (2 mL), Ethyl acetate, and wash with water, brine, and then dryover Na₂SO₄. Concentrate the organic mixture under reduced pressure toafford 293.0 mg (91% yield) of title compound as a white foam: ¹H NMR(500 MHz, CDCl₃); 1.4 (9H, s), 2.6-2.8 (2H, m), 3.2-3.4 (2H, m), 4.2-4.4(2H, m), 4.3-4.4 (2H, m), 6.9 (1H, d), 7.0-7.3 (9H, m), 8.3 (1H, d), 8.8(1H, s); MS m/z 349 (M−100, Boc).

Intermediate 286-(4-{[tert-Butoxycarbonyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinicacid

Using a method similar to Intermediate 27, using6-(4-{tert-Butoxycarbonyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinicacid ethyl ester (0.311 g, 0.73 mmol) gives 273.4 mg (92% yield) of thetitle compound: ¹H NMR (500 MHz, CDCl₃); 0.8-0.9 (6H, m), 1.3-1.6 (12H,m), 3.0-3.3 (2H, m), 3.8 (3H, s), 4.3-4.5 (2H, m), 6.9 (1H, d), 7.0-7.4(5H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 315 (M−100, Boc).

Intermediate 29[4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamic acidtert-butyl ester

Combine6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinicacid (0.097 g, 0.21 mmol), CH₂Cl₂ (5 mL), EDC (0.048 g, 0.25 mmol), HOBt(0.034 g, 0.25 mmol), Hunig's Base (92 uL, 0.53 mmol), and MethylamineHydrochloride (0.014 g, 0.21 mmol) in a 7 mL reaction vial. Afterreactions shake for 72 hours, add 10% Citric acid, followed by 10%NaHCO₃, and then add the organic mixture to a Celite column. Elute withCH₂Cl₂, concentrate, and flash chromatograph using 2:1 Ethylacetate:Hexanes eluent to afford 55.4 mg (57% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.0(3H, s), 4.2-4.4 (2H, m), 4.3-4.5 (2H, m), 6.3-6.4 (1H, br s), 6.9 (1H,d), 7.0-7.4 (9H, m), 8.1 (1H, d), 8.6 (1H, s); MS m/z 362 (M−100, Boc).

Intermediate 30 [4-(5-Ethylcarbamoyl-pyridin-2-yloxy]-phenethyl-carbamicacid tert-butyl ester

Using a method similar to Intermediate 29, using Ethylamine, 2.0 M inMeOH (0.11 mL, 0.21 mmol) gives 72.3 mg (72% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 0.2 (3H, t), 1.4 (9H, m), 2.7-2.9(2H, m), 3.3-3.5 (4H, m), 4.2-4.4 (2H, m), 6.2 (1H, br s), 6.9 (1H, d),7.0-7.4 (9H, m), 8.1 (1H, d), 8.6 (1H, s); MS m/z 376 Boc).

Intermediate 31[4-(5-Isopropylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamicacid tert-butyl ester

Using a method similar to Intermediate 29, using Isopropylamine, (18.0uL, 0.21 mmol) gives 70.6 mg (69% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 1.2 (6H, d), 1.4 (9H, s), 2.6-2.8 (2H, m), 3.2-3.4(2H, m), 4.2-4.4 (3H, m), 5.9 (1H, d), 6.8 (1H, d), 6.9-7.0 (9H, m), 8.0(1H, d), 8.4 (1H, s); MS m/z 390 (M−100, Boc).

Intermediate 32(3-Methyl-butyl)-[4-(5-methylcarbamoyl-pyridin-2-yloxy)-benzyl]-carbamicacid tert-butyl ester

Combine6-(4-{[tert-Butoxycarbonyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinicacid (0.090 g, 0.21 mmol), CH₂Cl₂ (5 mL), EDC (0.048 g, 0.25 mmol), HOBt(0.034 g, 0.25 mmol), Hunig's Base (92 uL, 0.53 mmol), and MethylamineHydrochloride (0.014 g, 0.21 mmol) in a 7 mL reaction vial. Afterreactions shake for 72 hours, add 10% Citric acid, followed by 10%NaHCO₃, and then add the organic mixture to a Celite column. Elute withCH₂Cl₂, concentrate, and flash chromatograph using 2:1 Ethylacetate:Hexanes eluent to afford 56.2 mg (63% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 0.9 (6H, d), 1.3-1.6 (12H, m), 3.0(3H, s), 3.1-3.3 (2H, m), 4.3-4.5 (2H, m), 6.3 (1H, br s), 6.9 (1H, d),7.1 (2H, d), 7.2-7.4 (2H, m), 8.1 (1H, d), 8.5 (1H, s); MS m/z 328(M−100, Boc).

Intermediate 33

[4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-carbamicacid tert-butyl ester

Using a method similar to Intermediate 42, using Ethylamine, 2.0 M inMeOH (0.11 mL, 0.21 mmol) gives 66.7 mg (72% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 0.9 (6H, d), 1.2 (3H, t), 1.3-1.6(12H, m), 3.1-3.3 (2H, m), 3.4-3.5 (2H, m), 4.3-4.5 (2H, m), 6.2 (1H, brs), 6.9 (1H, d), 7.1 (2H, d), 7.2-7.4 (2H, m), 8.1 (1H, d), 8.5 (1H, s);MS m/z 328 (M−100, Boc).

Intermediate 34[4-(5-Isopropylcarbamoyl-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-carbamicacid tert-butyl ester

Using a method similar to Intermediate 42, using Isopropylamine, (18.0uL, 0.21 mmol) gives 66.7 mg (41% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 0.9 (6H, d), 1.3 (6H, d), 1.3-1.6 (12H, m), 3.1-3.4(2H, m), 4.2-4.3 (1H, m), 4.3-4.5 (2H, m), 5.9 (2H, br s), 6.9 (1H, d),7.1 (2H, d), 7.2-7.4 (3H, m), 8.1 (1H, d), 8.5 (1H, s); MS m/z 328(M−100, Boc).

EXAMPLE 816 N-Ethyl-6-[4-(phenethylamino-methyl)-phenoxy]-nicotinamide

Using a method similar to Example 770, using[4-(5-Ethylcarbamoyl-pyridin-2-yloxy]-phenethyl-carbamic acid tert-butylester (72.3 mg, 0.15 mmol) gives 45.6 mg (80% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 1.2 (3H, t), 2.8-3.0 (4H, m), 3.4-3.6(2H, m), 3.8 (2H, s), 6.1 (1H, br s), 6.9 (1H, d), 7.0-7.4 (9H, m), 8.1(1H, d), 8.5 (1H, s); MS m/z 376 (M+1).

EXAMPLE 817N-Isopropyl-6-[4-(phenethylamino-methyl)-phenoxy]-nicotinamide

Using a method similar to Example 770, using[4-(5-Isopropylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamicacid tert-butyl ester (70.6 mg, 0.14 mmol) gives 64.5 mg (99% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 1.3 (6H, d), 2.8-3.0 (4H,m), 3.8 (2H, s), 4.2-4.4 (1H, m), 5.9 (1H, ds), 6.9 (1H, d), 7.0-7.4(9H, m), 8.1 (1H, d), 8.5 (1H, s); MS m/z 390 (M+1).

EXAMPLE 818N-Methyl-6-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 770, using(3-Methyl-butyl)-[4-(5-methylcarbamoyl-pyridin-2-yloxy)-benzyl]-carbamicacid tert-butyl ester (56.2 mg, 0.13 mmol) gives 33.9 mg (79% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 0.9 (6H, d), 1.3-1.5 (2H,m), 1.5-1.8 (2H, br m), 2.7 (2H, t), 2.9-3.0 (4H, m), 3.8 (2H, s), 6.2(1H, br s), 6.9 (1H, d), 7.1 (2H, d), 7.2-7.4 (2H, m), 8.1 (1H, d), 8.5(1H, s); MS m/z 328 (M+1).

EXAMPLE 819N-Ethyl-6-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 770, using[4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-carbamicacid tert-butyl ester (66.7 mg, 0.15 mmol) gives 44.4 mg (86% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 0.9 (6H, d), 1.2 (3H, t),1.3-1.5 (2H, m), 1.6-1.7 (1H, m), 2.6 (2H, t), 3.4-3.6 (2H, m), 3.8 (2H,s), 6.2 (1H, br s), 6.9 (1H, d), 7.1 (2H, d), 7.2-7.4 (2H, m), 8.1 (1H,d), 8.5 (1H, s); MS m/z 342 (M+1).

EXAMPLE 820N-Isopropyl-6-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

Using a method similar to Example 770 using[4-(5-Isopropylcarbamoyl-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-carbamicacid tert-butyl ester (39.6 mg, 0.09 mmol) gives 26.0 mg (84% yield) ofthe title compound: ¹H NMR (500 MHz, CDCl₃); 0.9 (6H, d), 1.3 (6H, d),1.4-1.5 (2H, m), 1.5-1.7 (2H, m), 2.7 (2H, t), 3.8 (2H, s), 4.2-4.3 (1H,m), 5.9 (1H, br s), 6.9 (1H, d), 7.1 (2H, d), 7.2-7.4 (3H, m), 8.1 (1H,d), 8.5 (1H, s); MS m/z 356 (M+1).

Intermediate 35 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethylester

Combine Ethyl nipecotate (9.9 mL, 63.6 mmol), K₂CO₃ (13.2 g, 95.4 mmol),and DMF (300 mL) at room temperature under a Nitrogen atmosphere. Heatreaction mixture to 70° C. for 30 minutes then add 4-Methoxybenzylchloride (9.5 mL, 69.9 mmol). Stir the reaction for 5 hours at 70° C.then cool the reaction mixture to room temperature and stir for anadditional 12 hours. Add Ethyl acetate to the reaction mixture andextract with water and then brine. Dry the organic layer over Na₂SO₄.Concentrate under reduced pressure and flash chromatograph using 3:1Hexanes:Ethyl acetate to give 14.6 g (82% yield) of the title compound:¹H NMR (500 MHz, CDCl₃); 1.2 (3H, t), 1.4-1.6 (2H, m), 1.6-1.7 (1H, m),1.9-2.1 (2H, m), 2.2 (1H, t), 1.5-1.8 (2H, m), 2.9 (1H, d), 3.5 (2H, q),3.8 (3H, s), 4.1 (2H, dd), 6.8 (2H, d), 7.2 (2H, d); MS m/z 278 (M+1).

Intermediate 36 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acidmethoxy-methyl-amide

Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester(9.3 g, 33.5 mmol), THF (200 mL), N,O-Dimethylhydroxylaminehydrochloride (4.9 g, 50.3 mmol) at −10° C. (Acetone/ice bath) under aNitrogen atmosphere. By dropwise addition, add Isopropylmagnesiumchloride (50.3 mL, 100.6 mmol). Stir the reaction for 6 hours allowingthe reaction mixture to warm to room temperature. Quench the reactionmixture with sat NH₄Cl (aq) and extract product from the water usingEthyl acetate. Wash the organic layer with brine and then dry overNa₂SO₄. Concentrate under reduced pressure and flash chromatograph using1:1 Hexanes:Ethyl acetate and then 1:1 Hexanes:Ethyl acetate with 3% 1NNH₃MeOH to give 9.13 g (93% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.4-1.7 (3H, m), 1.8 (1H, d), 1.9 (1H, t), 2.1 (1H, t),2.8-3.0 (3H, m), 3.1 (3H, s), 3.5 (2H, d), 3.6 (3H, s), 3.8 (3H, s), 6.8(2H, d), 7.2 (2H, d); MS m/z 293 (M+1).

Intermediate 37 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-1-oneNF7-A00855-198.

Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acidmethoxy-methyl-amide (416.0 mg, 1.42 mmol) and THF (10 mL) at −78° C.under a Nitrogen atmosphere. By dropwise addition, add Ethylmagnesiumbromide (0.56 mL, 1.7 mmol). Stir the reaction for 12 hours allowing thereaction mixture to warm to room temperature and then add anotheraddition of Ethylmagnesium bromide (0.56 ml, 1.7 mmol) at roomtemperature. After the reaction stirs for 1 hour, quench the reactionmixture with sat NH₄Cl (aq) and extract product from the water usingEthyl acetate. Wash the organic layer with brine and then dry overNa₂SO₄. Concentrate under reduced pressure and add to an SCX (5 g)column pre-treated with 5% AcOH/MeOH. Wash with MeOH and elute productusing 1N NH₃ MeOH to give 280.6 mg (76% yield) of the title compound: ¹HNMR (500 MHz, d-MeOH); 0.9 (3H, q), 1.2-1.4 (1H, m), 1.5-1.7 (1H, m),1.7-1.8 (1H, m), 1.9 (1H, d), 1.9-2.1 (2H, m), 2.4-2.5 (2H, m), 2.6-2.7(1H, m), 2.8 (1H, d), 2.9 (1H, d), 3.5 (2H, s), 3.8 (3H, s), 6.8 (2H,d), 7.2 (2H, d); MS m/z 262 (M+1).

Intermediate 38 1-(4-Methoxy-benzyl)-3-propyl-piperidine

Combine 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-1-one (277.3 mg,1.07 mmol), Diethylene glycol (10 mL), KOH (178.0 mg, 3.18 mmol), andHydrazine-monohydrate (1.0 mL) at room temperature under a Nitrogenatmosphere. Heat the reaction mixture to 120° C. for 2 hours and then220° C. for 4 hours. Cool reaction to room temperature and then pour thereaction mixture over sat NH₄Cl (aq). Extract with Ethyl acetate, washwith brine, and dry over Na₂SO₄. Concentrate under reduced pressure andflash chromatograph using 3% 1N NH₃ MeOH in CH₂Cl₂ to give 105.2 mg (40%yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.9 (3H, t),1.1-1.4 (4H, m), 1.5-1.7 (3H, m), 1.7 (1H, d), 1.9 (1H, td), 2.7-2.9(2H, m), 3.5 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 248(M+1).

EXAMPLE 821 6-[4-(3-Propyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 1-(4-Methoxy-benzyl)-3-propyl-piperidine (105.2 mg, 0.43 mmol),Ethanol (50 mL), 20% Pd(OH)₂/C (75.0 mg), and a Hydrogen at 30° C. under50-60 psi for 12 hours on a Parr shaker. Filter the reaction mixture andthen add 5% AcOH/MeOH (3 mL), 6-(4-Formyl-phenoxy)-nicotinonitrile(Intermediate 51) (40.0 mg, 0.31 mmol), and NaCNBH₃ (83.7 mg, 0.34mmol). Stir the reaction at room temperature for 72 hours and thenconcentrate the reaction mixture under reduced pressure. Add thereaction mixture to an SCX Column (2 g), wash with methanol, and elutewith 1N NH₃ MeOH. Concentrate under reduced pressure and flashchromatograph using 3% 1N NH₃ MeOH in CH₂Cl₂ to give 19.8 mg (18% yield)of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.8-0.9 (4H, m), 1.0-1.4(5H, m), 1.5-1.8 (4H, m), 1.9-2.1 (1H, br s), 2.8-3.0 (2H, br s),3.4-3.7 (2H, br d), 6.9 (1H, d), 7.1 (2H, d), 7.3-7.5 (2H, m), 8.1 (1H,d), 8.6 (1H, s); MS m/z 354 (M+1).

Intermediate 39 6-(4-Formyl-phenoxy)-nicotinonitrile

Combine 4-Hydroxybenzaldehyde (8.0 g, 65.5 mmol),6-Chloronicotinonitrile (9.07 g, 65.5 mmol), powdered K₂CO₃ (13.6 g,98.3 mmol), and DMA/Toluene (80/240 mL) in a 500 mL RB flask equippedwith a stir, reflux condenser, and a Dean Stark Trap. Reflux thereaction mixture for several hours under a Nitrogen atmosphere then coolto room temperature and quench with sat NH₄Cl (aq). Add Ethyl acetate toextract the product and wash several times with water and then brine.Dry the organic layer over Na₂SO₄. Concentrate and flash chromatographusing 2:1 Hexanes:Ethyl acetate to give 13.2 g (88% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃); 7.1 (1H, d), 7.3-7.4 (2H, m), 7.9-8.0(3H, m), 8.5 (1H, d), 10.0 (1H, s); MS m/z 225 (M+1).

Intermediate 40 6-(4-Formyl-phenoxy)-nicotinamide

Combine 6-(4-Formyl-phenoxy)-nicotinonitrile (3.02 g, 13.5 mmol),powdered K₂CO₃ (0.93 g, 6.7 mmol), and DMSO (100 mL) in a RB flask andadd H₂O₂, 30% wt. Aq (4.05 mL, 13.5 mmol) by dropwise addition at 0° C.Stir the reaction mixture for 3 hours allowing it to come to roomtemperature then quench the reaction slowly at 0° C. with water. Extractthe product out of the water layer with ethyl acetate several times andthen wash with brine. Dry over Na₂SO₄ and concentrate under reducedpressure to give 2.78 g (95% yield) of the title compound: ¹H NMR (500MHz, DMSO); 7.2 (1H, d), 7.3-7.4 (2H, m), 7.5 (1H, br s), 7.9-8.0 (2H,m), 8.1 (1H, br s), 8.3 (1H, d), 8.7 (1H, s), 10.0 (1H, s); MS m/z 243(M+1).

Intermediate 41 2-{1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-2-ol

Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester(1.36 g, 4.9 mmol) and THF (10 mL) at −10° C. (Acetone/ice bath) under aNitrogen atmosphere. By dropwise addition, add Methylmagnesium bromide(6.5 mL, 19.6 mmol). Stir the reaction for 3 hours at room temperatureand then quench the reaction mixture with sat NH₄Cl (aq) and extractproduct from the water using Ethyl acetate. Wash the organic layer withbrine and then dry over Na₂SO₄. Concentrate under reduced pressure andflash chromatograph using 3% 1N NH₃-MeOH in CH₂Cl₂ to give 832.0 mg (65%yield) of the title compound: ¹H NMR (500 MHz, d-MeOH); 1.1 (6H, d),1.4-1.7 (2H, m), 1.7-2.0 (4H, m), 2.8 (1H, d), 3.1 (1H, d), 3.4 (1H, s),3.5 (2H, d), 3.8 (2H, s), 4.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z264 (M+1).

Intermediate 42 3-Isopropylidene-1-(4-methoxy-benzyl)-piperidine

Combine 2-{1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-2-ol (0.564 g,2.14 mmol) and 1:1 Et₃SiH:TFA (8 mL) at room temperature. Reflux thereaction for 72 hours under a Nitrogen atmosphere and then concentrateunder reduced pressure and flash chromatograph using 3% 1N NH₃-MeOH inCH₂Cl₂ to give 400.0 mg (76% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.5-1.6 (8H, d), 2.2 (2H, t), 2.5 (2H, br s), 3.0 (2H, brs), 3.5 (2H, br s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 246

EXAMPLE 8226-[4-(3-Isopropyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 3-Isopropylidene-1-(4-methoxy-benzyl)-piperidine (227.0 mg, 0.92mmol), Ethanol (50 mL), 20% Pd(OH)₂/C (75.0 mg), and a Hydrogen at 30°C. under 50-60 psi for 12 hours on a Parr shaker. Filter the reactionmixture and then add 5% AcOH/MeOH (3 mL),6-(4-Formyl-phenoxy)-nicotinonitrile (Intermediate 51) (104.0 mg, 0.43mmol), and NaCNBH₃ (49.0 mg, 0.78 mmol). Stir the reaction at roomtemperature for 72 hours and then concentrate the reaction mixture underreduced pressure. Add the reaction mixture to an SCX Column (2 g), washwith methanol, and elute with 1N NH₃ MeOH. Concentrate under reducedpressure and purify by reverse phase chromatography using 5 to 95%0.001% TFA in CH₃CN/H₂O to give 37.2 mg (11% yield) of the titlecompound: ¹H NMR (500 MHz, d-MeOH); 0.9 (6H, dd), 0.9-1.1 (1H, m),1.3-1.6 (3H, m), 1.7-1.9 (3H, m), 1.9-2.0 (1H, m), 2.9 (1H, d) 3.0 (1H,d), 3.5 (2H, dd), 6.9 (1H, d), 7.1 (2H, d), 7.4 (2H, d), 8.2 (1H, d),8.6 (1H, s); MS m/z 354 (M+1).

Intermediate 43 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-butan-1-one

Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acidmethoxy-methyl-amide (401.0 mg, 1.37 mmol) and THF (10 mL) at 0° C.under a Nitrogen atmosphere. By dropwise addition, add Propylmagnesiumchloride (4.0 mL, 8.22 mmol). Reflux the reaction for 5 hours then coolthe reaction to room temperature and quench the reaction mixture withsat NH₄Cl (aq) and extract product from the water using Ethyl acetate.Wash the organic layer with brine and then dry over Na₂SO₄. Concentrateunder reduced pressure and add to an SCX (5 g) column pre-treated with5% AcOH/MeOH. Wash with MeOH and elute product using 1N NH₃ MeOH to give356.0 mg (94% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.8(3H, t), 1.3 (1H, qd), 1.4-1.5 (3H, m), 1.6-1.8 (1H, m), 1.9 (1H, dd),2.0 (1H, td), 2.1 (1H, t), 2.4 (2H, t), 2.5-2.6 (1H, m), 2.7 (1H, d),2.9 (1H, d), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); TLC 4%1N NH₃ MeOH:CH₂Cl₂ R_(f)=0.42.

Intermediate 44 3-Butyl-1-(4-methoxy-benzyl)-piperidine

Combine 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-butan-1-one (356.0 mg,0.95 mmol), Diethylene glycol (15 mL), KOH (479.0 mg, 8.54 mmol), andHydrazine-monohydrate (1.8 mL) at room temperature under a Nitrogenatmosphere. Heat the reaction mixture to 120° C. for 2 hours and then220° C. for 24 hours. Cool reaction to room temperature and then pourthe reaction mixture over sat NH₄Cl (aq). Extract with Ethyl acetate,wash with brine, and dry over Na₂SO₄. Concentrate under reduced pressureand flash chromatograph using 3% 1N NH₃MeOH in CH₂Cl₂ to give 220.7 mg(89% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.7-0.9 (3H,m), 1.1-1.4 (4H, m), 1.5-1.7 (4H, m), 1.7 (1H, d), 1.9 (1H, t), 2.8 (2H,t), 3.4 (2H, dd), 3.6-3.7 (3H, m), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H,d); MS m/z 262 (M+1).

EXAMPLE 822 6-[4-(3-Butyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 822, using3-Butyl-1-(4-methoxy-benzyl)-piperidine (220.7 mg, 0.89 mmol) gives 24.6mg (9% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.8-0.9(4H, m), 1.1-1.4 (6H, m), 1.5-1.7 (4H, m), 1.8 (1H, d), 1.9 (1H, t),2.9-3.0 (2H, m), 3.5 (2H, dd), 5.9-6.2 (2H, br s), 6.9 (1H, d), 7.1 (2H,d), 7.3-7.4 (2H, m), 8.2 (1H, d), 8.5 (1H, s); MS m/z 368 (M+1).

Intermediate 45 1-[1-(Methoxy-benzyl)-piperidin-3-yl]-ethanone

Using a method similar to Intermediate 43, using Methylmagnesium bromide(7.4 mL, 22.16 mmol) gives 1.37 g (73% yield) of the title compound: ¹HNMR (500 MHz, CDCl₃); 1.4 (1H, qd), 1.5-1.6 (1H, m), 1.6-1.7 (1H, m),1.8-1.9 (1H, m), 2.0 (1H, td), 2.1 (3H, s), 2.5-2.6 (1H, m), 2.7 (2H,d), 2.9 (1H, d), 3.5 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MSm/z 248 (M+1).

Intermediate 46 3-Ethyl-1-(4-methoxy-benzyl)-piperidine

Using a method similar to intermediate 44, using1-[1-(Methoxy-benzyl)-piperidin-3-yl]-ethanone (1.0 g, 4.03 mmol) gives388.3 mg (42% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃);0.8-0.9 (4H, m), 1.1-1.2 (2H, m), 1.4-1.6 (4H, m), 1.7 (1H, d), 1.9 (1H,td), 2.8 (2H, t), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d);MS m/z 234 (M+1).

EXAMPLE 824 6-[4-(3-Ethyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Using a method similar to Example 822, using3-Ethyl-1-(4-methoxy-benzyl)-piperidine (388.3 mg, 1.66 mmol) gives 45.8mg (21% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃); 0.8-0.9(4H, m), 1.1-1.3 (2H, m), 1.4-1.6 (4H, m), 1.7 (1H, d), 1.9 (1H, t), 2.8(2H, t), 3.5 (2H, dd), 6.0-6.2 (2H, br s), 6.9 (1H, d), 7.1 (2H, d),7.3-7.4 (2H, m), 8.2 (1H, d), 8.5 (1H, s); MS m/z 340 (M+1).

EXAMPLE 8256-[4-(3,3-Dimethyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 5% AcOH/MeOH (3 mL), 6-(4-Formyl-phenoxy)-nicotinonitrile(Intermediate 51) (242.24 mg, 1.0 mmol), and NaCNBH₃ (113.1 mg, 1.8mmol). Stir the reaction at room temperature for 3 hours and thenconcentrate the reaction mixture under reduced pressure. Add thereaction mixture to an SCX Column (2 g), wash with methanol, and elutewith 1N NH₃MeOH. Concentrate under reduced pressure and purify byreverse phase chromatography using 5 to 95% 0.001% TFA in CH₃CN/H₂O togive 168.0 mg (55% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 0.9 (6H, s), 1.2-1.3 (2H, m), 1.1.5-1.8 (4H, m), 2.0-2.1 (2H,m), 2.2-2.4 (2H, m), 3.4-3.5 (2H, m), 6.9 (1H, d), 7.1 (1H, d), 7.2 (1H,d), 7.4 (1H, d), 7.5 (1H, d), 8.2 (1H, d), 8.6 (1H, d); MS m/z 340(M+1).

EXAMPLE 8266-[4-(3-Trifluoromethyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 5% AcOH/MeOH (3 mL), 6-(4-Formyl-phenoxy)-nicotinonitrile(Intermediate 51) (120.0 mg, 0.33 mmol), and NaCNBH₃ (184.0 mg, 0.46mmol). Stir the reaction at room temperature for 12 hours and thenconcentrate the reaction mixture under reduced pressure. Add thereaction mixture to an SCX Column (2 g), wash with methanol, and elutewith 1N NH₃MeOH. Concentrate under reduced pressure and purify byreverse phase chromatography using 5 to 95% 0.001% TFA in CH₃CN/H₂O togive 46.6 mg (26% yield) of the title compound: ¹H NMR (500 MHz,d-MeOH); 1.2-1.4 (1H, m), 1.5-1.7 (1H, m), 1.7-1.9 (1H, m), 1.9-2.1 (2H,m), 2.3-2.5 (1H, m), 2.9 (1H, d), 3.1 (1H, d), 3.6 (2H, s), 6.9 (1H, d),7.1 (2H, d), 7.4 (2H, d), 8.2 (1H, d), 8.6 (1H, d): MS m/z 380 (M+1).

EXAMPLE 8276-[4-(3-Spiro-[1-(3,4-dihydro)naphthalene]-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

Combine 5% AcOH/MeOH (3 mL), 6-(4-Formyl-phenoxy)-nicotinonitrile(Intermediate 51) (126.4 mg, 0.52 mmol), and NaCNBH₃ (65.3 mg, 1.04mmol). Stir the reaction at room temperature for 12 hours and thenconcentrate the reaction mixture under reduced pressure. Add thereaction mixture to an SCX Column (2 g), wash with methanol, and elutewith 1N NH₃MeOH. Concentrate under reduced pressure and purify byreverse phase chromatography using 5 to 95% 0.001% TFA in CH₃CN/H₂O togive 105.2 mg (47% yield) of the title compound: ¹H NMR (500 MHz,d-MeOH); 1.5-1.8 (5H, m), 1.9-2.0 (2H, m), 2.1-2.2 (2H, m), 2.3-2.4 (1H,m), 2.5-2.8 (3H, m), 2.9 (1H, d), 3.3-3.4 (2H, m), 3.5-3.6 (1H, m),6.9-7.2 (7H, m), 7.3-7.5 (2H, m), 8.2 (1H, d), 8.6 (1H, d); MS m/z 428(M+1).

1. A compound selected from the group consisting of:6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinamide

5-{2-Fluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-pyrazine-2-carboxamide

5-(2-Methoxy-4-pentylaminomethyl-phenoxy)-pyrazine-2-carboxamide

6-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide

6-(2,3-Difluoro-4-pentylaminomethyl-phenoxy)-nicotinamide

5-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-pyrazine-2-carboxamide

5-{4-[(4,4-Dimethyl-pentylamino)-methyl]-2-methoxy-phenoxy}-pyrazine-2-carboxamide

5-(2-Methoxy-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

5-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-phenoxy}-pyrazine-2-carboxamide

5-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

6-{2-Methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

5-(2-Methyl-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

6-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-6-methoxy-phenoxy}-nicotinamide

5-(2-Fluoro-4-pentylaminomethyl-phenoxy)-pyrazine-2-carboxamide

3-Chloro-4-{4-[(3,3-dimethyl-butylamino)-methyl]-phenoxy}-benzamide

6-(4-{[2-(Tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide

6-{4-[2-(3,3-Dimethyl-butylamino)-ethyl]-2,6-difluoro-phenoxy}-nicotinamide

6-{2-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

3,5-Difluoro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

6-{2,3,6-Trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

6-{2,6-Difluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamide

3-Fluoro-4-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-benzamide

or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1which is 6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinamide

or a pharmaceutically acceptable salt thereof.
 3. A hydrochloric acidsalt of the compound of claim 2 which is6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinamide hydrochloride


4. A compound of claim 1 which is5-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-pyrazine-2-carboxamide

or a pharmaceutically acceptable salt thereof.
 5. A compound of claim 1which is 5-(2-Methoxy-4-pentylaminomethyl-phenoxy)-pyrazine-2-carboxylicacid amide

or a pharmaceutically acceptable salt thereof.
 6. A compound of claim 1which is5-(2-Methoxy-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide

or a pharmaceutically acceptable salt thereof.
 7. A compound of claim 1which is6-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-nicotinamide

or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound according to claim 1 in associationwith a carrier, diluent and/or excipient.
 9. A compound of claim 1 whichis5-(2-Methoxy-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide,hydrochloric acid salt


10. A compound of claim 1 which is5-(2-Fluoro-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide,hydrochloric acid salt